Carbamate/urea derivatives

ABSTRACT

The invention relates to compound of the formula I 
     
       
         
         
             
             
         
       
     
     or a salt thereof, wherein the substituents are as defined in the specification; to its preparation, to its use as medicament and to medicaments comprising it.

The invention relates to carbamate/urea derivatives, to their solidforms, to their preparation, to their use as medicaments and tomedicaments comprising them.

I. Carbamate/Urea Derivatives

Histamine is a multifunctional chemical transmitter that signals throughspecific cell surface G-protein-coupled receptors (GPCRs). To date, fourhistamine receptors subtypes have been identified: H1, H2, H3 and H4.The H3 receptor is a presynaptic GPCR that is found predominantly in thecentral nervous system, although lower levels are also found in theperipheral nervous system. Genes encoding the H3 receptor have beenreported in various organisms, including humans, and alternativesplicing of this gene appears to result in multiple isoforms. The H3receptor is an auto- and heteroreceptor whose activation leads to adecreased release of neurotransmitters (including histamine,acetylcholine, norepinephrine, dopamine and glutamate) from neurons inthe brain, and is involved in the regulation of processes such as sleepand wakefulness, feeding and memory. In certain systems, the H3 receptormay be constitutively active.

Antagonists of H3 receptor increase release of cerebral histamine andother neurotransmitters, which in turn induces an extended wakefulness,an improvement in cognitive processes, a reduction in food intake and anormalization of vestibular reflexes. H3 receptor antagonists aredescribed e.g. in Lazewska and Kiec-Kononowicz, Expert Opin TherPatents, 2010, 20(9), 1147-1169; Raddatz et al, Current Topics inMedicinal Chemistry, 2010, 10, 153-169; WO2007052124; WO2007016496 andWO2004101546.

As histamine pathways have been implicated in a wide range of disorders,in particular disorders of sleep and wakefulness with excessive daytimesleepiness, e.g. narcolepsy, H3 receptor antagonists are considered tobe useful for pharmacotherapy of said disorders.

There is a need to provide new H3 receptor antagonists that are gooddrug candidates. In particular, preferred compounds should bind potentlyto H3 receptors whilst showing little affinity for other receptors, e.g.receptors mediating significant side-effects, such as hERG channelswhich may induce cardiovascular side-effects. They should be wellabsorbed from the gastrointestinal tract, be sufficiently metabolicallystable, possess favorable pharmacokinetic properties, sufficient brainuptake, fast onset and sufficiently long duration of action. For e.g.narcolepsy treatment, the pharmacokinetic property of the compoundshould lead to good wakefulness during daytime, but should equally leadto a minimal impact on night-sleep. The drug candidates should benon-toxic and demonstrate few side-effects. Furthermore, the ideal drugcandidate will be able to exist in a physical form that is stable,non-hygroscopic and easily formulated.

The compounds of the invention are H3 receptor antagonists and aretherefore potentially useful in the treatment of a wide range ofdisorders, particularly narcolepsy.

In a first aspect, the invention relates to a compound of the formula I

or a salt thereof, whereinR₁ is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkinyl, C₃₋₆cycloalkyl,C₅₋₆cycloalkenyl or C₃₋₆cycloalkyl-C₁₋₄alkyl; wherein said C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkinyl or C₃₋₆cycloalkyl-C₁₋₄alkyl may be substitutedonce or more than once by halogen; and wherein said C₃₋₆cycloalkyl orC₅₋₆cycloalkenyl may be substituted once or more than once by halogen,C₁₋₄alkyl or C₁₋₄halogenalkyl;m is 1 or 2;n is 0, 1, 2, 3 or 4;each R₂ independently is halogen, hydroxyl, amino, cyano, nitro,C₁₋₆alkyl, C₁₋₆halogenalkyl, C₁₋₆hydroxyalkyl, C₁₋₄alkoxy-C₁₋₆alkyl,amino-C₁₋₆alkyl, C₁₋₄alkyl-amino-C₁₋₆alkyl,di(C₁₋₄alkyl)-amino-C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆halogenalkoxy,di(C₁₋₆alkyl)amino, C₂₋₆alkenyl, C₂₋₆halogenalkenyl, C₂₋₆alkinyl orC₂₋₆halogenalkinyl;or C₃₋₆cycloalkyl, wherein one carbon atom may be replaced by an oxygenatom, wherein the C₃₋₆cycloalkyl may be attached directly to themethylene or via a C₁₋₂alkylene, and wherein the C₃₋₆cycloalkyl may besubstituted once or more than once by halogen;or two R₂ at the same carbon atom form together with said carbon atom aC₃₋₆cycloalkyl;X₁ is oxygen or —N(R₄)—;R₄ is hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, or C₃₋₆cycloalkyl-C₁₋₂alkyl;p is 1 and q is 1;p is 0 and q is 1; orp is 0 and q is 0;r is 0, 1, 2, 3 or 4;each R₃ independently is halogen, hydroxyl, amino, cyano, nitro,C₁₋₆alkyl, C₁₋₆halogenalkyl, C₁₋₆hydroxyalkyl, C₁₋₄alkoxy-C₁₋₆alkyl,amino-C₁₋₆alkyl, C₁₋₄alkyl-amino-C₁₋₆alkyl,di(C₁₋₄alkyl)-amino-C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆halogenalkoxy,di(C₁₋₆alkyl)amino, C₂₋₆alkenyl, C₂₋₆halogenalkenyl, C₂₋₆alkinyl orC₂₋₆halogenalkinyl;or C₃₋₆cycloalkyl, wherein one carbon atom may be replaced by an oxygenatom, wherein the C₃₋₆cycloalkyl may be attached directly to themethylene or via a C₁₋₂alkylene, and wherein the C₃₋₆cycloalkyl may besubstituted once or more than once by halogen;or two R₃ at the same carbon atom form together with said carbon atom aC₃₋₆cycloalkyl;

A is

wherein the bond marked with the asterisk is attached to the nitrogenatom;R₅ is hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkinyl, C₃₋₆cycloalkyl,C₆₋₆cycloalkenyl or C₃₋₆cycloalkyl-C₁₋₄alkyl; wherein said C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkinyl or C₃₋₆cycloalkyl-C₁₋₄alkyl may be substitutedonce or more than once by halogen, hydroxyl or C₁₋₆alkoxy; and whereinsaid C₃₋₆cycloalkyl or C₅₋₆cycloalkenyl may be substituted once or morethan once by halogen, C₁₋₄alkyl or C₁₋₄halogenalkyl;X₂ is nitrogen or carbon;s is 0, 1, 2 or 3;each R₆ independently is halogen, hydroxyl, amino, cyano, nitro,C₁₋₆alkyl, C₁₋₆halogenalkyl, C₁₋₆hydroxyalkyl, C₁₋₄alkoxy-C₁₋₆alkyl,di(C₁₋₄alkyl)-amino-C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆halogenalkoxy,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, C₂₋₆alkenyl, C₂₋₆halogenalkenyl,C₂₋₆alkinyl or C₂₋₆halogenalkinyl;or C₃₋₆cycloalkyl, wherein one carbon atom may be replaced by an oxygenatom, wherein the C₃₋₆cycloalkyl may be attached directly to themethylene or via a C₁₋₂alkylene, and wherein the C₃₋₆cycloalkyl may besubstituted once or more than once by halogen.

Unless specified otherwise, the term “compounds of the invention” refersto compounds of formula (I) and subformulae thereof (e.g. compounds offormula (I-1)); prodrugs thereof; solid forms of free forms or salts ofthe compounds, e.g. SOLID FORMS OF THE INVENTION, and/or prodrugs;hydrates or solvates of the compounds, salts and/or prodrugs; as well asall stereoisomers (including diastereoisomers and enantiomers),tautomers and isotopically labeled compounds (including deuteriumsubstitutions); as well as inherently formed moieties (e.g. polymorphs,solvates and/or hydrates).

Unless indicated otherwise, the expressions used in this invention havethe following meaning:

“Alkyl” represents a straight-chain or branched-chain alkyl group and,for example, may be methyl, ethyl, n- or iso-propyl, n-, iso-, sec- ortert-butyl, n-pentyl, n-hexyl; C₁₋₆alkyl preferably represents astraight-chain or branched-chain C₁₋₄alkyl with particular preferencegiven to methyl, ethyl, n-propyl, iso-propyl and tert-butyl.

Each alkyl part of “alkoxy”, “halogenalkyl” and so on shall have thesame meaning as described in the above-mentioned definition of “alkyl”,especially regarding linearity and preferential size.

“C₃₋₆cycloalkyl” represents a saturated alicyclic moiety having fromthree to six carbon atoms. This term refers to groups such ascyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

A substituent being substituted “once or more than once”, e.g. asdefined in connection with R₁, is preferably substituted by one to threesubstituents.

Halogen is generally fluorine, chlorine, bromine or iodine; preferablyfluorine, chlorine or bromine. Halogenalkyl groups preferably have achain length of 1 to 4 carbon atoms and are, for example, fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl,pentafluoroethyl, 1,1-difluoro-2,2,2-trichloroethyl,2,2,2-trichloroethyl, 1,1,2,2-tetrafluoroethyl,2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl or2,2,3,4,4,4-hexafluorobutyl.

In the event X₂ being carbon, said carbon can be unsubstituted,substituted by a R₆ or used to attach A to the nitrogen of theneighbouring piperidine/pyrrolidine/azetidine moiety.

Compounds of formula I may exist in optically active form or in form ofmixtures of optical isomers, e.g. in form of racemic mixtures ordiastereomeric mixtures. In particular, asymmetrical carbon atom(s) maybe present in the compounds of formula I and their salts. Unlessotherwise provided herein, all optical isomers and their mixtures,including the racemic mixtures, are embraced by the invention.

As used herein, the term “isomers” refers to different compounds thathave the same molecular formula but differ in arrangement andconfiguration of the atoms. Also as used herein, the term “an opticalisomer” or “a stereoisomer” refers to any of the various stereo isomericconfigurations which may exist for a given compound of the invention andincludes geometric isomers. It is understood that a substituent may beattached at a chiral center of a carbon atom. The term “chiral” refersto molecules which have the property of non-superimposability on theirmirror image partner, while the term “achiral” refers to molecules whichare superimposable on their mirror image partner. Therefore, theinvention includes enantiomers, diastereomers or racemates of thecompound. “Enantiomers” are a pair of stereoisomers that arenon-superimposable mirror images of each other. A 1:1 mixture of a pairof enantiomers is a “racemic” mixture. The term is used to designate aracemic mixture where appropriate. “Diastereoisomers” are stereoisomersthat have at least two asymmetric atoms, but which are not mirror-imagesof each other. The absolute stereochemistry is specified according tothe Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomerthe stereochemistry at each chiral carbon may be specified by either Ror S. Resolved compounds whose absolute configuration is unknown can bedesignated (+) or (−) depending on the direction (dextro- orlevorotatory) which they rotate plane polarized light at the wavelengthof the sodium D line. The compounds described herein may contain one ormore asymmetric centers and may thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that may be defined, interms of absolute stereochemistry, as (R)- or (S)-. Unless otherwiseprovided herein, the invention is meant to include all such possibleisomers, including racemic mixtures, optically pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques.

If the compound contains a double bond, the substituent may be E or Zconfiguration.

If the compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans-configuration.

Any asymmetric atom (e.g. carbon or the like) of the compound(s) of theinvention can be present in racemic or enantiomerically enriched, forexample the (R)-, (S)- or (R,S)-configuration. In certain embodiments,each asymmetric atom has at least 50% enantiomeric excess, at least 60%enantiomeric excess, at least 70% enantiomeric excess, at least 80%enantiomeric excess, at least 90% enantiomeric excess, at least 95%enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or(S)-configuration. Substituents at atoms with unsaturated bonds may, ifpossible, be present in cis- (Z)- or trans-(E)-form.

Accordingly, as used herein, a compound of the invention can be in theform of one of the possible isomers, rotamers, atropisomers, tautomersor mixtures thereof, for example, as substantially pure geometric (cisor trans) isomers, diastereomers, optical isomers (antipodes), racematesor mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the invention into their opticalantipodes, e.g., by fractional crystallization of a salt formed with anoptically active acid, e.g., tartaric acid, dibenzoyl tartaric acid,diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelic acid,malic acid or camphor-10-sulfonic acid. Racemic products can also beresolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Depending on substituent definition, compounds of formula I may occur invarious tautomeric forms. All tautomeric forms of the compounds offormula I are embraced by the invention.

As used herein, the terms “salt” or “salts” refers to an acid additionor base addition salt of a respective compound, e.g. a compound of theinvention or of a compound of formula II-1. “Salts” include inparticular “pharmaceutically acceptable salts”. The term“pharmaceutically acceptable salts” refers to salts that retain thebiological effectiveness and properties of the compounds of thisinvention and, which typically are not biologically or otherwiseundesirable. The compounds of the invention may be capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the invention can besynthesized from a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, use of non-aqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile is desirable, wherepracticable. Lists of additional suitable salts can be found, e.g., in“Remington's Pharmaceutical Sciences”, 20th ed., Mack PublishingCompany, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

When both a basic group and an acid group are present in the samemolecule, the compounds of the invention may also form internal salts,e.g., zwitterionic molecules.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵Irespectively. The invention includes various isotopically labeledcompounds as defined herein, for example those into which radioactiveisotopes, such as ³H and ¹⁴C, or those into which non-radioactiveisotopes, such as ²H and ¹³C are present. Such isotopically labelledcompounds are useful in metabolic studies (with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques,such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or labeled compound may be particularly desirable forPET or SPECT studies. Isotopically-labeled compounds of formula (I) cangenerally be prepared by conventional techniques known to those skilledin the art or by processes analogous to those described in theaccompanying Examples and Preparations using an appropriateisotopically-labeled reagents in place of the non-labeled reagentpreviously employed.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the formula (I). The concentration of sucha heavier isotope, specifically deuterium, may be defined by theisotopic enrichment factor. The term “isotopic enrichment factor” asused herein means the ratio between the isotopic abundance and thenatural abundance of a specified isotope. If a substituent in a compoundof this invention is denoted deuterium, such compound has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Compounds of the invention that contain groups capable of acting asdonors and/or acceptors for hydrogen bonds may be capable of formingco-crystals with suitable co-crystal formers. These co-crystals may beprepared from compounds of formula (I) by known co-crystal formingprocedures. Such procedures include grinding, heating, co-subliming,co-melting, or contacting in solution compounds of formula I with theco-crystal former under crystallization conditions and isolatingco-crystals thereby formed. Suitable co-crystal formers include thosedescribed in WO 2004/078163. Hence the invention further providesco-crystals comprising a compound of formula (I).

The invention also provides pro-drugs of the compounds of the inventionthat convert in vivo to the compounds of the invention. A pro-drug is anactive or inactive compound that is modified chemically through in vivophysiological action, such as hydrolysis, metabolism and the like, intoa compound of the invention following administration of the prodrug to asubject. The suitability and techniques involved in making and usingpro-drugs are well known by those skilled in the art. See The Practiceof Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, SanDiego, Calif., 2001).

Furthermore, the compounds of the invention, including their salts, canalso be obtained in the form of their hydrates, or include othersolvents used for their crystallization. The compounds of the inventionmay inherently or by design form solvates with pharmaceuticallyacceptable solvents (including water); therefore, it is intended thatthe invention embrace both solvated and unsolvated forms. The term“solvate” refers to a molecular complex of a compound of the invention(including pharmaceutically acceptable salts thereof) with one or moresolvent molecules. Such solvent molecules are those commonly used in thepharmaceutical art, which are known to be innocuous to the recipient,e.g., water, ethanol, and the like. The term “hydrate” refers to thecomplex where the solvent molecule is water.

The compounds of the invention, including salts, hydrates and solvatesthereof, may inherently or by design form polymorphs.

Preferred substituents, preferred ranges of numerical values orpreferred ranges of the radicals present in compounds of the formula Iand the corresponding intermediate compounds are defined below. Thedefinition of the substituents applies to the end-products as well as tothe corresponding intermediates. The definitions of the substituents maybe combined at will, e.g. preferred substituents A and particularlypreferred substituents R₁.

In one embodiment, the invention provides a compound of formula I,wherein R₁ is C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂alkyl.

In one embodiment, the invention provides a compound of formula I,wherein R₁ is C₃₋₄alkyl or C₃₋₅cycloalkyl.

In one embodiment, the invention provides a compound of formula I,wherein R₁ is isopropyl, cyclopropyl, cyclobutyl or cyclopentyl.

In one embodiment, the invention provides a compound of formula I,wherein R₁ is isopropyl.

In one embodiment, the invention provides a compound of formula I,wherein R₁ is cyclobutyl.

In one embodiment, the invention provides a compound of formula I,wherein m is 1.

In one embodiment, the invention provides a compound of formula I,wherein m is 2.

In one embodiment, the invention provides a compound of formula I,wherein n is 0, 1 or 2 and wherein each R₂ independently is halogen,C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄alkoxy, C₁₋₄halogenalkoxy orC₃₋₄cycloalkyl; or two R₂ at the same carbon atom form together withsaid carbon atom a C₃₋₄cycloalkyl.

In one embodiment, the invention provides a compound of formula I,wherein n is O.

In one embodiment, the invention provides a compound of formula I,wherein X₁ is oxygen.

In one embodiment, the invention provides a compound of formula I,wherein X₁ is —N(R₄)— and R₄ is hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, orC₃₋₆cycloalkyl-C₁₋₂alkyl.

In one embodiment, the invention provides a compound of formula I,wherein X₁ is —N(R₄)— and R₄ is hydrogen.

In one embodiment, the invention provides a compound of formula I,wherein p is 1 and q is 1.

In one embodiment, the invention provides a compound of formula I,wherein p is 0 and q is 1.

In one embodiment, the invention provides a compound of formula I,wherein p is 0 and q is 0.

In one embodiment, the invention provides a compound of formula I,wherein r is 0, 1 or 2 and wherein each R₃ independently is halogen,C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄alkoxy, C₁₋₄halogenalkoxy orC₃₋₄cycloalkyl; or two R₃ at the same carbon atom form together withsaid carbon atom a C₃₋₄cycloalkyl.

In one embodiment, the invention provides a compound of formula I,wherein r is 0.

In one embodiment, the invention provides a compound of formula I,wherein A is A1

wherein the bond marked with the asterisk is attached to the nitrogenatom.

In one embodiment, the invention provides a compound of formula I,wherein A is A1;

R₅ is hydrogen, C₁₋₄alkyl, C₁₋₄halogenalkyl or C₃₋₄cycloalkyl;s is 0, 1 or 2; andeach R₆ independently is halogen, C₁₋₄alkyl, C₁₋₄halogenalkyl,C₁₋₄alkoxy, C₁₋₄halogenalkoxy or C₃₋₄cycloalkyl.

In one embodiment, the invention provides a compound of formula I,wherein A is A1, R₅ is hydrogen or methyl, and s is 0.

In one embodiment, the invention provides a compound of formula I,wherein A is A2

wherein the bond marked with the asterisk is attached to the nitrogenatom;and s is 0, 1 or 2.

In one embodiment, the invention provides a compound of formula I,wherein A is A2;

R₅ is hydrogen, C₁₋₄alkyl, C₁₋₄halogenalkyl or C₃₋₄cycloalkyl;s is 0, 1 or 2; andeach R₆ independently is halogen, C₁₋₄alkyl, C₁₋₄halogenalkyl,C₁₋₄alkoxy, C₁₋₄halogenalkoxy or C₃₋₄cycloalkyl.

In one embodiment, the invention provides a compound of formula I,wherein A is A2, R₅ is hydrogen or methyl, and s is 0.

In one embodiment, the invention provides a compound of formula I,wherein A is A3

wherein the bond marked with the asterisk is attached to the nitrogenatom.

In one embodiment, the invention provides a compound of formula I,wherein A is A3;

R₅ is hydrogen, C₁₋₄alkyl, C₁₋₄halogenalkyl or C₃₋₄cycloalkyl;s is 0, 1 or 2; andeach R₆ independently is halogen, C₁₋₄alkyl, C₁₋₄halogenalkyl,C₁₋₄alkoxy, C₁₋₄halogenalkoxy or C₃₋₄cycloalkyl.

In one embodiment, the invention provides a compound of formula I,wherein A is A3, R₅ is hydrogen or methyl, and s is 0.

In one embodiment, the invention provides a compound of formula I,wherein A is A4

wherein the bond marked with the asterisk is attached to the nitrogenatom;and s is 0, 1 or 2.

In one embodiment, the invention provides a compound of formula I,wherein A is A4;

R₅ is hydrogen, C₁₋₄alkyl, C₁₋₄halogenalkyl or C₃₋₄cycloalkyl;s is 0, 1 or 2; andeach R₆ independently is halogen, C₁₋₄alkyl, C₁₋₄halogenalkyl,C₁₋₄alkoxy, C₁₋₄halogenalkoxy or C₃₋₄cycloalkyl.

In one embodiment, the invention provides a compound of formula I,wherein A is A4, R₅ is hydrogen or methyl, and s is 0.

In one embodiment, the invention provides a compound of formula I,wherein

R₁ is isopropyl or cyclobutyl; m is 1; n is 0, 1 or 2; each R₂independently is halogen, C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄alkoxy,C₁₋₄halogenalkoxy or C₃₋₄cycloalkyl; or two R₂ at the same carbon atomform together with said carbon atom a C₃₋₄cycloalkyl;X₁ is oxygen;p is 1 and q is 1; r is 0, 1 or 2; wherein each R₃ independently ishalogen, C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄alkoxy, C₁₋₄halogenalkoxy orC₃₋₄cycloalkyl; or two R₃ at the same carbon atom form together withsaid carbon atom a C₃₋₄cycloalkyl; A is selected from A3 and A4

wherein the bond marked with the asterisk is attached to the nitrogenatom;R₅ is hydrogen or methyl;s is 0, 1 or 2; andeach R₆ independently is halogen, C₁₋₄alkyl, C₁₋₄halogenalkyl,C₁₋₄alkoxy, C₁₋₄halogenalkoxy or C₃₋₄cycloalkyl.

In one embodiment, the invention provides a compound of formula I,wherein

R₁ is isopropyl or cyclobutyl; m is 1 and n is 0;X₁ is oxygen;

p is 1 and q is 1; r is 0; and A is

is selected from A3 and A4

wherein the bond marked with the asterisk is attached to the nitrogenatom;and R₅ is hydrogen or methyl; and s is 0.

In one embodiment, the invention provides a compound of formula I,wherein

R₁ is C₁₋₆alkyl or C₃₋₆cycloalkyl;m is 1 and n is 0;X₁ is oxygen;p is 1 and q is 1; r is 0; and

A is

wherein the bond marked with the asterisk is attached to the nitrogenatom;X₂ is nitrogen or carbon;R₅ is hydrogen or C₁₋₆alkyl; and s is 0.

In one embodiment, the invention provides a compound of formula I,wherein

R₁ is C₁₋₆alkyl or C₃₋₆cycloalkyl;m is 1 and n is 0;X₁ is oxygen;p is 1 and q is 1; r is 0; andA is selected from A3 and A4

wherein the bond marked with the asterisk is attached to the nitrogenatom;R₅ is hydrogen or C₁₋₆alkyl; and s is 0.

In one embodiment, the invention provides a compound of formula I,wherein

R₁ is isopropyl, cyclopropyl or cyclobutyl;m is 1 and n is 0;X₁ is oxygen;p is 1 and q is 1; r is 0; and

A is

wherein the bond marked with the asterisk is attached to the nitrogenatom;X₂ is nitrogen or carbon;R₅ is hydrogen, methyl or ethyl; and s is 0.

In one embodiment, the invention provides a compound of formula I,wherein

R₁ is isopropyl, cyclopropyl or cyclobutyl;m is 1 and n is 0;X₁ is oxygen;p is 1 and q is 1; r is 0; and A is selected from A3 and A4

wherein the bond marked with the asterisk is attached to the nitrogenatom;R₅ is hydrogen, methyl or ethyl; and s is 0.

In preferred embodiments, the invention relates to one or more than oneof the compounds of the formula I mentioned in the Examples hereinafteror to a salt thereof.

Further examples of suitable compounds of the invention are compoundsselected from the following group P:

Group P: Suitable Compounds of the Invention:

-   1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl    4-cyclobutylpiperazine-1-carboxylate;-   1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl    4-isopropylpiperazine-1-carboxylate;-   1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl    4-isopropylpiperazine-1-carboxylate;-   1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl    4-cyclopropylpiperazine-1-carboxylate;-   1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl    4-cyclobutylpiperazine-1-carboxylate;-   1-(1-ethyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl    4-isopropylpiperazine-1-carboxylate;-   1-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)piperidin-4-yl    4-isopropylpiperazine-1-carboxylate;-   1-(2-oxo-1,2-dihydropyridin-4-yl)piperidin-4-yl    4-cyclobutylpiperazine-1-carboxylate;-   1-(2-oxo-1,2-dihydropyridin-4-yl)piperidin-4-yl    4-isopropylpiperazine-1-carboxylate; or-   1-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-4-yl    4-isopropylpiperazine-1-carboxylate;    or salts of these compounds.

In a further aspect, the invention also provides a process for theproduction of compounds of the formula I-1. Compounds of the formula I-1are obtainable according to the following process as described in scheme1:

A compound of formula I-1, in which A, R₁, R₂, R₃, m, n, p, q and r areas defined under formula I, may be obtained by reacting a compound offormula II-1, in which A, R₃, p, q and r are as defined under formula Iand R_(a) is a leaving group, e.g. halogen, such as chloro, or4-nitrophenyloxy (preferably R_(a) is 4-nitrophenyloxy), with a compoundof formula III, in which R₁, R₂, m and n are as defined under formula I,in the presence of a suitable base, e.g. diisopropylethylamine, in thepresence of a suitable solvent, e.g. pyridine.

In a further aspect, the invention also provides a process for theproduction of compounds of the formula I-2. Compounds of the formula I-2are obtainable according to the following process as described in scheme2:

A compound of formula I-2, in which A, R₁, R₂, R₃, m, n, p, q and r areas defined under formula I, may be obtained by reacting a compound offormula II-2, in which A, R₃, p, q and r are as defined under formula I,with a compound of formula III, in which in which R₁, R₂, m and n are asdefined under formula I, in the presence of carbonyldiimidazole, asuitable base, e.g. diisopropylethylamine, and a suitable solvent, e.g.dimethylformamide.

Further compounds of formula I or their precursors may be obtainablefrom compounds of formula I-1 or I-2, prepared as described according toscheme 1 or 2, or their precursors (e.g. compounds of formulae II-1,II-2 and/or III) by reduction, oxidation and/or other functionalizationof resulting compounds and/or by cleavage of any protecting group(s)optionally present, and of recovering the so obtainable compound of theformula I. Compounds of the formula I can also be prepared by furtherconventional processes, e.g. as described in the Examples, whichprocesses are further aspects of the invention.

The invention also contemplates that compounds of formula (I) may beformed by in vivo biotransformation from pro-drugs.

The reactions can be effected according to conventional methods, forexample as described in the Examples.

The work-up of the reaction mixtures and the purification of thecompounds thus obtainable may be carried out in accordance with knownprocedures.

Acid addition salts may be produced from the free bases in known manner,and vice-versa.

Starting materials, e.g. compounds of the formulae II-1, II-2 and IIImay be known or prepared according to conventional procedures startingfrom known compounds, for example as described in the Examples.

In a further aspect, the invention also provides a process for theproduction of compounds of the formula II-1. Compounds of the formulaII-1 are obtainable according to the following process as described inscheme 3:

Step 3.1:

A compound of formula V-1, in which A, R₃, p, q and r are as definedunder formula I, may be obtained by reacting a compound of formulaVII-1, in which R₃, p, q and r are as defined under formula I, with acompound of formula VI, in which A is as defined under formula I andR_(b) is halogen, for example chloro, in the presence of a suitablebase, e.g. diisopropylethylamine, and optionally in the presence of asuitable solvent.

Step 3.2:

A compound of formula II-1, in which A, R₁, R₂, R₃, m, n, p, q and r areas defined under formula I, may be obtained by reacting the compound ofV-1 with a compound of formula IV, in which R_(c) is halogen, forexample chloro, and R_(a) is a leaving group, e.g. halogen or4-nitrophenyloxy (preferably R_(a) is 4-nitrophenyloxy), in the presenceof a suitable base, e.g. diisopropylethylamine, and in the presence of asuitable solvent, e.g. pyridine.

In a further aspect, the invention also provides a novel compound offormula II-1

or a salt thereof; in which p, q, r, R₃ and A are as defined underformula I; R_(a) is a leaving group, e.g. halogen, such as chloro, or agroup selected from

wherein the bond marked with the asterisk is attached to the carbonylgroup;wherein R′ is hydrogen or nitro; preferably R_(a) is 4-nitrophenyloxy.

In one embodiment of said further aspect, the invention provides acompound of formula II-1, wherein

p is 1 and q is 1;p is 0 and q is 1; orp is 0 and q is 0;r is 0, 1 or 2 and wherein each R₂ independently is halogen, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, C₁₋₄halogenalkoxy or C₃₋₄cycloalkyl; ortwo R₂ at the same carbon atom form together with said carbon atom aC₃₋₄cycloalkyl; and

A is A4 or A5.

In one embodiment of said further aspect, the invention provides acompound of formula II-1, wherein R₁ is isopropyl; m is 1; X₁ is oxygen;p is 1 and q is 1; n is 0; p is 1 and q is 1; A is A4 or A5; and R₅ ishydrogen or methyl,

In one embodiment of said further aspect, the invention provides acompound of formula II-1, wherein R₁ is cyclobutyl; m is 1; X₁ isoxygen; p is 1 and q is 1; n is 0; p is 1 and q is 1; A is A4 or A5; andR₅ is hydrogen or methyl,

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of the invention and a pharmaceutically acceptablecarrier. The pharmaceutical composition can be formulated for particularroutes of administration such as oral administration, parenteraladministration, and rectal administration, etc. In addition, thepharmaceutical compositions of the invention can be made up in a solidform including capsules, tablets, pills, granules, powders orsuppositories, or in a liquid form including solutions, suspensions oremulsions. The pharmaceutical compositions can be subjected toconventional pharmaceutical operations such as sterilization and/or cancontain conventional inert diluents, lubricating agents, or bufferingagents, as well as adjuvants, such as preservatives, stabilizers,wetting agents, emulsifers and buffers etc.

Typically, the pharmaceutical compositions are tablets and gelatincapsules comprising the active ingredient together with

-   -   a) diluents, e.g., lactose, dextrose, sucrose, mannitol,        sorbitol, cellulose and/or glycine;    -   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium        or calcium salt and/or polyethyleneglycol; for tablets also    -   c) binders, e.g., magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone; if desired    -   d) disintegrants, e.g., starches, agar, alginic acid or its        sodium salt, or effervescent mixtures; and/or    -   e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets contain the active ingredient in admixture withnontoxic pharmaceutically acceptable excipients which are suitable forthe manufacture of tablets.

These excipients are, for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example, starch, gelatin oracacia; and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets are uncoated or coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatecan be employed. Formulations for oral use can be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example, peanut oil, liquidparaffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with carrier. Carriers includeabsorbable pharmacologically acceptable solvents to assist passagethrough the skin of the host. For example, transdermal devices are inthe form of a bandage comprising a backing member, a reservoircontaining the compound optionally with carriers, optionally a ratecontrolling barrier to deliver the compound of the skin of the host at acontrolled and predetermined rate over a prolonged period of time, andmeans to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art. Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

As used herein a topical application may also pertain to an inhalationor to an intranasal application. They are conveniently delivered in theform of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurised container, pump, spray, atomizer ornebuliser, with or without the use of a suitable propellant.

The invention further provides anhydrous pharmaceutical compositions anddosage forms comprising the compounds of the invention as activeingredients, since water may facilitate the degradation of certaincompounds.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. An anhydrous pharmaceuticalcomposition may be prepared and stored such that its anhydrous nature ismaintained. Accordingly, anhydrous compositions are preferably packagedusing materials known to prevent exposure to water such that they can beincluded in suitable formulary kits. Examples of suitable packaginginclude, but are not limited to, hermetically sealed foils, plastics,unit dose containers (e.g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the invention as an active ingredient will decompose. Suchagents, which are referred to herein as “stabilizers,” include, but arenot limited to, antioxidants such as ascorbic acid, pH buffers, or saltbuffers, etc.

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drugs, drug stabilizers, binders, excipients,disintegration agents, lubricants, sweetening agents, flavoring agents,dyes, such like materials and combinations thereof, as would be known toone of ordinary skill in the art (see, for example, Remington'sPharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp.1289-1329). Except insofar as any conventional carrier is incompatiblewith the active ingredient, its use in the therapeutic or pharmaceuticalcompositions is contemplated.

The compounds of formula I or pharmaceutical acceptable salts thereofexhibit valuable pharmacological properties and are therefore useful aspharmaceuticals.

Furthermore, compounds of formula I may be useful for research on H3receptors, e.g. as tool compounds.

In particular, compounds of formula I exhibit a H3 receptor antagonisticaction at human H3 receptors.

As used herein, the term “H3 receptor antagonist” encompasses H3receptor inverse agonists and H3 receptor neutral antagonists.

H3 receptor antagonistic action can be determined in vitro, for example,at recombinant human H3 receptors, using different procedures like, forexample, measurement of the inhibition of the agonist induced elevationof intracellular cAMP concentration, e.g. as described herein.

The compounds of the invention may be therefore useful in theprevention, treatment or delay of progression of disorders mediated byH3 receptors.

Disorders mediated by H3 receptors may be for example

i) disorders of sleep and wakefulness with excessive daytime sleepiness;such as narcolepsy, e.g. narcolepsy with or without cataplexy; secondarynarcoleptic syndromes; central sleep apnea syndrome; or obstructivesleep apnea syndrome;ii) disorders or conditions associated with increased fatigue orhypersomnolence; such as fatigue associated with autoimmune disease,e.g. Multiple Sclerosis or Rheumatoid Arthritis; fatigue associated withneurodegenerative disorders, e.g. as Parkinson's disease, Multisystematrophy, Shy-Drager-Syndrome or Progressive Supranuclear Palsy; fatigueassociated with other medical conditions or their treatment, such asdepression, burnout syndrome, or adjustment disorder; stress-associateddisorders with fatigue, e.g. acute stress disorder or posttraumaticstress disorder; cancer-associated fatigue; chemotherapy-associatedfatigue; fatigue associated with shift-work; jet lag; chronic fatiguesyndrome; fibromyalgia; postinfectious fatigue; postoperative fatigue ordizziness;iii) disorders or conditions with impaired cognition; such as AlzheimersDisease; Mild Cognitive Impairment; Diffuse-Lewy body dementia; vasculardementia; Huntington's disease; Wilson's disease; frontotemporaldementia; other forms of organic dementia or organic cognitiveimpairment; multiple sclerosis; schizophrenia; schizoaffective disorder;bipolar-affective disorder;iv) disorders of substance abuse or addiction; such as to alcohol,cocaine, opioids, cannabinoids, nicotine or other substances with abuseor addiction potential;v) non-substance abuse conditions; such as pathological gambling;vi) disorders associated with dysfunctional feeding behaviours and/ormetabolic syndrome; such as antipsychotic drug-associated weight gain;Prader-Willi-Sndrome; Moon-Bardet-Biedl Syndrome; obesity; atypicaldepression; bulimia nervosa; or binge eating disorder;vii) disorders with increased anxiety; such as general anxiety disorder;social anxiety disorder; or panic disorder;viii) other neuropsychiatric or neurological disorders; such as Tourettesyndrome; primary tic disorders; secondary tic disorders; attentiondeficit hyperactivity disorders; obsessive-compulsive disorders;headache disorders, e.g. episodic migraine, chronic migraine, clusterheadache, or tension-type headache; acute disorders associated withneuronal loss, e.g. stroke; REM-sleep behavioural disorder;restless-legs syndrome; or epilepsy;ix) other medical conditions or disorders; such as disorders withimpaired hearing; vertigo; Menieres Disease; itch; pruritus;inflammatory pain; neuropathic pain; diabetes mellitus; cancer;atherosclerosis; allergies; or allergic rhinitis;

Of particular importance is the treatment of narcolepsy; fatigueassociated with multiple sclerosis; fatigue associated with Parkinson'sdisease; cognitive impairment associated with schizophrenia; cognitiveimpairment associated with Alzheimer's disease; mild cognitiveimpairment; Tourette syndrome; or Attention-deficit hyperactivitydisorder.

For the above-mentioned indications (the conditions and disorders) theappropriate dosage will vary depending upon, for example, the compoundemployed, the host, the mode of administration and the nature andseverity of the condition being treated. However, in general,satisfactory results in animals are indicated to be obtained at a dailydosage of from about 0.001 to about 500 mg/kg body weight, preferablyfrom about 0.1 to about 10 mg/kg body weight, e.g. 1 mg/kg. In largermammals, for example humans, an indicated daily dosage is in the rangefrom about 0.1 to about 1000 mg, preferably from about 0.1 to about 400mg, most preferably from about 0.1 to about 100 mg of the compound ofthe invention conveniently administered, for example, in divided dosesup to four times a day.

For use according to the invention, a compound of the invention may beadministered as single active agent or in combination with other activeagents, in any usual manner, e.g. orally, for example in the form oftablets or capsules, or parenterally, for example in the form ofinjection solutions or suspensions. A combination comprising a compoundof the invention and one or more other therapeutically active agentswill be referred to as “combination of the invention”.

In the case of narcolepsy, the compound of the invention may be combinedat least with one active agent selected from the group consisting of

a noradrenaline-dopamine reuptake inhibitor, such as modafinil orarmodafinil;a tri- or tetracyclic antidepressant, such as clomipramine;a serotonin-noradrenaline reuptake inhibitor, such as venlafaxine orduloxetine;a selective serotonin reuptake inhibitor, such as paroxetine;a noradrenaline reuptake inhibitor, such as reboxetine or atomoxetine;a MAO-B inhibitor such as selegiline;a gamma-hydroxy-butyrate; anda psychostimulant, such as methylphenidate.

Said combination of the invention is useful to treat narcolepsy.

In the case of fatigue associated with multiple sclerosis, the compoundof the invention may be combined at least with one active agent selectedfrom the group consisting of

a sphingosine-1-phosphate analog, such as fingolimod; andanother immunosuppressive agent, such as prednisolone or methotrexate.

In the case of fatigue associated with Parkinson's disease, the compoundof the invention may be combined at least with one active agent selectedfrom the group consisting of L-Dopa with or without a Decarboxylaseinhibitor, such as Benzerazid or Carbidopa, and/or with or without acatechol-O-Methylransferase inhibitor, such as entacapone or tolcapone;a dopamine receptor agonist, such as ropinirole or pergolide; and aMAO-B inhibitor, such as selegiline.

In the case of cognitive impairment associated with schizophrenia, thecompound of the invention may be combined at least with oneantipsychotic agent, such as haloperidol, olanzapine; risperidone;quetiapine; amisulpiride; or aripirazole.

In the case of cognitive impairment associated with Alzheimer's disease,the compound of the invention may be combined at least with one activeagent selected from the group consisting of

a cholinergic agent, such as an acetylcholinesterase inhibitor, e.g.donepezil, rivastigmine or galantamine; andan antiglutamatergic agent, such as memantine, selfotel or midafotel.

In the case of cognitive impairment associated with Alzheimer's disease,the compound of the invention may be combined at least with one activeagent selected from the group consisting of

a cholinergic agent, such as an acetylcholinesterase inhibitor,e.g.donepezil, rivastigmine or galantamine; andan antiglutamatergic agent, such as memantine.

In the case of Tourette's syndrome, the compound of the invention may becombined at least with one active agent selected from the groupconsisting of

an alpha receptor agonist, such as clonidine;an antipsychotic agent, such as fluphenazine, haloperidol, pimozide,aripirazole, of risperidone; anda dopamine depleting agent, such as tetrabenazine.

In the case of attention-deficit hyperactivity disorder, the compound ofthe invention may be combined at least with one active agent selectedfrom the group consisting of

a noradrenaline-dopamine reuptake inhibitor, such as modafinil orarmodafinil;a tri- or tetracyclic antidepressant, such as clomipramine;a psychostimulant, such as methylphenidate a noradrenaline-serotoninreuptake inhibitor, such as venlafaxine or duloxetine;a selective serotonin reuptake inhibitor, such as paroxetine; anda noradrenaline reuptake inhibitor, such as reboxetine or atomoxetine.

The compounds of the invention may be useful for the prevention of theabove-mentioned conditions and disorders.

The compounds of the invention may be useful for the treatment of theabove-mentioned conditions and disorders.

The compounds of the invention may be useful for the delay ofprogression of the above-mentioned conditions and disorders.

The usefulness of the compounds of the invention in the treatment of theabove-mentioned disorders can be confirmed in a range of standard testsincluding those indicated below:

The in vivo activity of the compounds of the invention can be assessedby measuring the effects on brain histamine release (quantification ofthe histamine metabolite tele-methylhistamine) and/or by testing theeffects on wakefulness in rats with EEG electrodes.

Compounds of the invention may be especially useful in the treatment ofan indication selected from: narcolepsy; fatigue associated withmultiple sclerosis; fatigue associated with Parkinson's disease;cognitive impairment associated with schizophrenia; cognitive impairmentassociated with Alzheimer's disease; mild cognitive impairment; Tourettesyndrome; and Attention-deficit hyperactivity disorder; very especiallynarcolepsy.

Thus, as a further embodiment, the invention provides the use of acompound of formula (I) or a pharmaceutically acceptable salt thereof asa medicament.

As a further embodiment, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof in therapy.

In a further embodiment, the therapy is selected from a disease which isameliorated by inhibition of H3 receptor action. In another embodiment,the disease is selected from the afore-mentioned list, e.g. is selectedfrom narcolepsy; fatigue associated with multiple sclerosis; fatigueassociated with Parkinson's disease; cognitive impairment associatedwith schizophrenia; cognitive impairment associated with Alzheimer'sdisease; mild cognitive impairment; Tourette syndrome; andAttention-deficit hyperactivity disorder; very especially narcolepsy.

In another embodiment, the invention provides a method of treating adisease which is ameliorated by inhibition of H3 receptors comprisingadministration of a therapeutically acceptable amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof. In a furtherembodiment, the disease is selected from the afore-mentioned list, e.g.is selected from narcolepsy; fatigue associated with multiple sclerosis;fatigue associated with Parkinson's disease; cognitive impairmentassociated with schizophrenia; cognitive impairment associated withAlzheimer's disease; mild cognitive impairment; Tourette syndrome; andAttention-deficit hyperactivity disorder; very especially narcolepsy.

The term “a therapeutically effective amount” of a compound of theinvention refers to an amount of the compound of the invention that willelicit the biological or medical response of a subject, for example,reduction or inhibition of an enzyme or a protein activity, orameliorate symptoms, alleviate conditions, slow or delay diseaseprogression, or prevent a disease, etc. In one non-limiting embodiment,the term “a therapeutically effective amount” refers to the amount ofthe compound of the invention that, when administered to a subject, iseffective to (1) at least partially alleviating, inhibiting, preventingand/or ameliorating a condition, or a disorder or a disease (i) mediatedby H3 receptors, or (ii) associated with H3 receptor activity, or (iii)characterized by abnormal activity of H3 receptors; or (2) reducing orinhibiting the activity of H3 receptors; or (3) reducing or inhibitingthe expression of H3 receptors. In another non-limiting embodiment, theterm “a therapeutically effective amount” refers to the amount of thecompound of the invention that, when administered to a cell, or atissue, or a non-cellular biological material, or a medium, is effectiveto at least partially reducing or inhibiting the activity of H3receptors; or at least partially reducing or inhibiting the expressionof H3 receptors.

As used herein, the term “subject” refers to an animal. Preferably, theanimal is a mammal. A subject also refers to for example, primates(e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats,mice, fish, birds and the like. In a preferred embodiment, the subjectis a human.

As used herein, the term “inhibition” or “inhibiting” refers to thereduction or suppression of a given condition, symptom, or disorder, ordisease, or a significant decrease in the baseline activity of abiological activity or process.

As used herein, the term “treating” or “treatment” of any disease ordisorder refers in one embodiment, to ameliorating the disease ordisorder (i.e., slowing or arresting or reducing the development of thedisease or at least one of the clinical symptoms thereof). In anotherembodiment “treating” or “treatment” refers to alleviating orameliorating at least one physical parameter including those which maynot be discernible by the patient. In yet another embodiment, “treating”or “treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers topreventing or delaying the onset or development or progression of thedisease or disorder.

The pharmaceutical composition or combination of the invention can be inunit dosage of about 1-1000 mg of active ingredient(s) for a subject ofabout 50-70 kg, or about 1-500 mg or about 1-250 mg or about 1-150 mg orabout 0.5-100 mg, or about 1-50 mg of active ingredients. Thetherapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of theinvention can be applied in vitro in the form of solutions, e.g.,preferably aqueous solutions, and in vivo either enterally,parenterally, advantageously intravenously, e.g., as a suspension or inaqueous solution. The dosage in vitro may range between about 10⁻³ molarand 10⁻⁹ molar concentrations. A therapeutically effective amount invivo may range depending on the route of administration, between e.g.about 0.001-500 mg/kg, or between e.g. about 0.1-100 mg/kg.

The activity of a compound of the invention can be assessed by in vitro& in vivo methods described herein.

The compound of the invention may be administered either simultaneouslywith, or before or after, at least one other therapeutic agent. Thecompound of the invention may be administered separately, by the same ordifferent route of administration, or together in the samepharmaceutical composition.

The following Examples illustrate the invention, but do not limit it.

Abbreviations:

BINAP (+/−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthylBoc di(tert-butyl) carbonateBTC triphosgeneDCM dichloromethaneDIPEA N-ethyl-N-isopropylpropan-2-amine (Diisopropylethylamine)

DMAP 4-Dimethylaminepyridine

EA ethyl acetateh hour(s)HPLC high pressure liquid chromatographyLCMS liquid chromatography mass spectroscopyMeOH methanolmin minute(s)NMR nuclear magnetic resonance spectrometryprep-HPLC preparative high pressure liquid chromatographyPd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)Rt retention timert room temperaturet-BuOK Potassium tert-butanolateTEA triethylamineTFA trifluoroacetic acidTHF tetrahydrofuran

LCMS conditions (%=percent by volume): Agilent 1200 HPLC/6110 SQ system;Mobile Phase: A: water (10 mM NH₄HCO₃) B: Acetonitrile; Gradient: 5% Bfor 0.2 min, increase to 95% B within 1.2 min; 95% B for 1.5 min, backto 5% B within 0.01 min; Flow Rate: 1.8 ml/min; Column: XBridge C18,4.6*50 mm, 3.5 um; Oven Temperature: 50° C.

¹H NMR Instruments: Bruker AVANCE III (500 MHz), Bruker AVANCE III (400MHz)

EXAMPLES Example 1.1 1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutyl piperazine-1-carboxylate (Method A)

a) tert-butyl 4-cyclobutylpiperazine-1-carboxylate

To a solution of compound tert-butyl piperazine-1-carboxylate (37.2 g,200 mmol) in ClCH₂CH₂Cl (500 mL) was added cyclobutanone (21 g, 300mmol) and NaBH(OAc)₃ (84.8 g, 400 mmol). The reaction mixture wasstirred at rt for 16 h, quenched with saturated aq. Na₂CO₃ (500 mL) andextracted with DCM (3×500 mL). The combined organic layers were washedwith brine (50 mL), dried, filtered and concentrated under reducedpressure to afford the desired compound tert-butyl4-cyclobutylpiperazine-1-carboxylate (48 g, 100%) [LCMS: Rt=1.67 min,m/z 241.2 (M+H)⁺].

b) 1-cyclobutylpiperazine hydrochloride

To the mixture of tert-butyl 4-cyclobutylpiperazine-1-carboxylate (48 g,200 mmol) in MeOH (100 mL) was added 2.0 M HCl in MeOH (400 mL)carefully at 0° C. The mixture was stirred at rt for 5 h, concentratedunder reduced pressure to afford the desired compound1-cyclobutylpiperazine hydrochloride (35 g, 82%) [LCMS: Rt=0.94 min, m/z141.3 (M+H)⁺].

c) 6-(4-hydroxypiperidin-1-yl)pyridazin-3(2H)-one

To a solution of 6-chloropyridazin-3(2H)-one (2.6 g, 20 mmol) in DIPEA(30 mL) was added piperidin-4-ol (2.4 g, 20 mmol) and the mixture wasstirred at 120° C. for 8 h. The reaction mixture was concentrated underreduced pressure to afford the crude product, which was further purifiedby silica gel chromatography (DCM/MeOH=20/1) to afford the titlecompound (3.9 g, 100%) as a yellow solid. [LCMS: Rt=0.77 min, m/z 196.2(M+H)⁺].

d) 4-nitrophenyl 1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-ylcarbonate

To a solution of 6-(4-hydroxypiperidin-1-yl)pyridazin-3(2H)-one (3.9 g,20 mmol) in pyridine (10 mL) was added DIPEA (3.87 g, 30.0 mmol) and4-nitrophenyl carbonochloridate (6.03 g, 30 mmol) and the resultingmixture was stirred at 30° C. for 2 h. The mixture was concentratedunder reduced pressure and the residue was purified by silica gelchromatography (DCM to DCM/MeOH=20/1) to afford the title compound (3.3g, 46%) as a white solid. [LCMS: Rt=1.47 min, m/z 361.1 (M+H)]⁺.

e) 1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate

To a solution of 4-nitrophenyl1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl carbonate (440 mg,1.22 mmol) in DCM (20 mL) was added TEA (616 mg, 6.1 mmol) and1-cyclobutylpiperazine (388 mg, 1.83 mmol). The resulting mixture wasstirred at 30° C. for 2 h before it was concentrated to dryness. Thetitle compound was obtained as a white solid after silica gelchromatography (DCM/MeOH=50/1 to 5/1) (410 mg, 93%). [¹H NMR (400 MHz,CDCl₃) (δ 11.20 (s, 1H), 7.20 (d, J=10 Hz, 1H), 6.87 (d, J=10 Hz, 1H),4.87˜4.92 (m, 1H), 3.45˜3.50 (m, 6H), 3.16˜3.23 (m, 2H), 2.68˜2.76 (m,1H), 2.29 (br, 4H), 1.72˜2.07 (m, 10H); LCMS: Rt=1.36 min, m/z 362.3(M+H)⁺.

Example 1.21-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl-4-isopropylpiperazine-1-carboxylate

a) 6-chloro-2-methylpyridazin-3(2H)-one

To a solution of 6-chloropyridazin-3(2H)-one (780 mg, 6 mmol) in CH₃CN(40 mL) was added Cs₂CO₃ (3.9 g, 12 mmol) and CH₃I (1 mL, 12 mmol) andthe reaction mixture was stirred at 70° C. overnight. Solid was removedby filtration and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel chromatography (hexane/EA=3/1) toafford the title compound as orange oil (6.5 g, 75%). [LCMS: Rt=1.43min, m/z 145.1 (M+H)⁺].

b) 6-(4-hydroxypiperidin-1-yl)-2-methylpyridazin-3(2H)-one

To a slurry of 6-chloro-2-methylpyridazin-3(2H)-one (1 g, 6.94 mmol) inDIPEA (20 mL) was added piperidin-4-ol (0.84 g, 8.33 mmol) and thereaction mixture was stirred at 120° C. overnight. The resulting mixturewas diluted with water (30 mL) and extracted with DCM (3×30 mL) toremove impurities. The aqueous phase was concentrated to dryness toafford the title compound as a yellow solid (1.2 g, 83%). [LCMS: Rt=1.07min, m/z 210.1 (M+H)]⁺.

c)1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl-4-nitrophenylcarbonate

To a solution of 6-(4-hydroxypiperidin-1-yl)-2-methylpyridazin-3(2H)-one(1.46 g, 7 mmol) in DCM (20 mL) was added 4-nitrophenylcarbonochloridate (2.11 g, 10.5 mmol) and DIPEA (1.81 g, 14 mmol) andthe mixture was stirred at rt overnight. The mixture was diluted withDCM (20 mL), washed with water (3×15 mL) and the organic layer wasconcentrated to afford the title compound as a yellow solid (1.2 g,46%). [LCMS: Rt=1.54 min, m/z=375.1 (M+H)]⁺.

d)1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl-4-isopropylpiperazine-1-carboxylate

To a solution of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-nitrophenylcarbonate (1.2 g, 3.2 mmol) in DCM (20 mL) was added1-isopropylpiperazine (0.6 g, 4.8 mmol) and TEA (5 mL) and the reactionmixture was stirred at rt overnight. The mixture was then washed withsaturated Na₂CO₃ (3×30 mL), dried and concentrated to give crudeproduct, which was purified by silica gel chromatography (PE/EA=1/1) toafford the title compound as a white solid (0.48 g, 41%). [¹H NMR(CDCl₃, 400 MHz): δ 7.13˜7.10 (d, J=10, 1H), 6.86˜6.84 (d, J=10, 1H),4.92˜4.88 (m, 1H), 3.66 (s, 3H), 3.51˜3.46 (br, 6H); 3.22˜3.16 (m, 2H);2.74˜2.70 (m, 1H), 2.49 (br, 4H), 1.99 (m, 2H), 1.75 (m, 2H), 1.04 (d,6H); LCMS Rt=1.40 min, m/z 364.2 (M+H)⁺].

Example 1.5 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate

a)1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-piperidin-4-yl-4-cyclobutyl-piperazine-1-carboxylate

To a solution of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-nitrophenylcarbonate (101 mg, 0.27 mmol) in 8 mL of DCM, was added DIEA (105 mg,0.81 mmol) and 1-cyclobutylpiperazine (56 mg, 0.40 mmol). The mixturewas stirred at rt over night before it was diluted with 30 mL of water,extracted with DCM (3*25 mL). The combined organic phase was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified via Flash (Biotage, reversed phase column C-18,MeOH/H₂O=5%-95%, 0.5% NH₄OH) to afford 20 mg of the desired compound asa white solid. [¹H NMR (CDCl₃,400 MHz): δ 7.12 (d, J=10, 1H), 6.85 (d,J=10, 1H), 4.94-4.88 (m, 1H), 3.67 (s, 3H), 3.52-3.46 (m, 6H), 3.23-3.17(m, 2H), 2.75-2.69 (m, 1H), 2.30 (b, 4H), 2.08-1.97 (m, 4H), 1.93-1.86(m, 2H), 1.82-1.68 (m, 4H); LCMS Rt=1.44 min, m/z 376.3 (M+H)⁺.

Example 2 Synthesis of1-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)piperidin-4-yl-4-isopropylpiperazine-1-carboxylate(Method B)

a) tert-butyl 4-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (10 g, 50mmol) in CH₃OH (100 mL) was added NaBH₄ (5.7 g, 150 mmol) portionwisecarefully and the mixture was stirred at rt for 3 h. The reaction wasquenched by carefully pouring into ice-water (100 mL) and organicsolvent was removed under reduced pressure. The aqueous phase wasneutralized to pH=7 with 1N HCl and extracted with DCM/MeOH (5×60 mL,v/v=10/1). The combined organic layers were washed with brine (30 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to afford the crude product (9.8 g, 97%) as a white solid.[LCMS: Rt=1.36 min, m/z 146.1 (M-Bu+H)]⁺.

a) 1-(tert-butoxycarbonyl)piperidin-4-yl4-isopropylpiperazine-1-carboxylate

To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (4.4 g,21.9 mmol) in DCM (100 mL) was carefully added DMAP (5.3 g, 43.8 mmol)and triphosgene (3.2 g, 10.95 mmol) portionwise. After stirring at rtfor 2 h, 1-isopropylpiperazine (3.3 g, 26 mmol) was added and thereaction mixture was stirred at rt for 5 h. The reaction was quenchedwith saturated NH₄Cl (100 mL) solution and the mixture was extractedwith DCM (3×100 mL). The combined organic layers were washed withsaturated NH₄Cl (2×100 mL) and brine (50 mL) sequentially, dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure toafford the title compound as a white solid (7.7 g, 99%). [LCMS: Rt=1.67min, m/z 356.3 (M+H)⁺].

b) piperidin-4-yl 4-isopropylpiperazine-1-carboxylate

To a solution of 1-(tert-butoxycarbonyl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate (7.7 g, 21.7 mmol) in DCM (30 mL) was added TFA(10 mL) and the reaction mixture was stirred at rt for 5 h. The solventwas removed under reduced pressure and the residue was re-dissolved inDCM/MeOH (100 mL, v/v=10/1). Then powder Na₂CO₃ was added and themixture was stirred at rt for 2 h. Excess Na₂CO₃ was removed byfiltration and the cake was washed with DCM (2×100 mL). The combinedfiltrates were concentrated under reduced pressure to afford the desiredcompound as yellow oil (5.5 g, 100%). [LCMS: Rt=1.12 min, m/z 256.2(M+H)⁺].

c)1-(2-oxo-1,2-dihydropyridin-4-yl)piperidin-4-yl-4-isopropylpiperazine-1-carboxylate

To a solution of 4-bromopyridin-2(1H)-one (173 mg, 1.0 mmol) in TEA (10mL) was added piperidin-4-yl-4-isopropylpiperazine-1-carboxylate (255mg, 1.0 mmol) and the mixture was stirred at 100° C. for 16 h. Aftercooling to rt, the mixture was concentrated under vacuum. The residuewas dissolved in DCM (50 mL) and the mixture was washed with saturatedNaHCO₃ solution (2×30 mL). The organic layer was dried and concentratedto afford the crude product (348 mg, 100%), which was used directly fornext step without further purification. [LCMS: Rt=1.27 min, m/z 349.2(M+H)⁺].

d)1-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)piperidin-4-yl-4-isopropylpiperazine-1-carboxylate

To a solution of 1-(2-oxo-1,2-dihydropyridin-4-yl)piperidin-4-yl4-isopropylpiperazine-1-carboxylate (348 mg, 1.0 mmol) in THF (10 mL)was added NaH (60% in mineral oil) (200 mg, 5.0 mmol) portionwise. Afterstirring at rt for 1 h, CH₃I (213 mg, 1.5 mmol) was added and thereaction mixture was stirred at rt for 5 h. The reaction was quenchedwith water (30 mL), extracted with DCM (3×30 mL), dried and concentratedto give crude product, which was further purified by prep-HPLC to affordthe title compound as a white solid (110 mg, 30%). [¹H NMR (500 MHz,CDCl₃) δ 7.07 (d, J=8.0 Hz, 1H), 5.90 (dd, J=8.0, 2.5 Hz, 1H), 5.77 (d,J=2.5 Hz, 1H), 4.89˜4.94 (m, 1H), 3.47˜3.52 (m, 6H), 3.44 (s, 3H),3.20˜3.25 (m, 2H), 2.68˜2.73 (m, 1H), 2.47 (br, 4H), 1.92˜1.98 (m, 2H),1.69˜1.76 (m, 2H), 1.04 (d, J=6.5 Hz, 6H); LCMS: Rt=1.31 min, m/z 363.3(M+H)⁺].

Example 31-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-4-yl-4-isopropylpiperazine-1-carboxylate(Method C)

a) 2-(benzyloxy)-5-bromopyridine

To a solution of 5-bromopyridin-2(1H)-one (1.28 g, 7.36 mmol) and Ag₂CO₃(3 g, 11.04 mmol) in toluene (50 mL) was added (bromomethyl)benzene(1.25 g, 7.36 mmol) dropwise and the reaction mixture was stirred at100° C. over night. The reaction mixture was filtered through a shortpad of silica gel and washed with DCM. The filtrate was concentrated toyield the title compound as light yellow oil (1.8 g, 95%).

b) 1-(6-(benzyloxy)pyridin-3-yl)piperidin-4-yl4-isopropylpiperazine-1-carboxy late

To a solution of 2-(benzyloxy)-5-bromopyridine (1.5 g, 5.6 mmol),piperidin-4-yl 4-isopropylpiperazine-1-carboxylate (2.15 g, 8.4 mmol) intoluene (30 mL) was added Pd₂(dba)₃ (1.57 g, 2.2 mmol), BINAP (2.79 g,4.4 mmol) and t-BuOK (3.78 g, 33.8 mmol). The reaction was stirred underthe microwave irradiation at 120° C. for 20 min. The mixture was dilutedwith EA (100 mL) and washed with water (3×50 mL). The organic phase wasseparated, dried and concentrated to dryness. The residue was taken intodilute HCl (pH=1, 100 mL) and the mixture was extracted with DCM (3×100mL) to remove impurities. The aqueous phase was made basic (pH=9-10)with solid Na₂CO₃ and extracted with DCM (3×100 mL). The combinedorganic layers were dried, concentrated and purified by silica gelchromatography (EA/MeOH=50/1) to give the title compound as a whitesolid (500 mg, 20%). [LCMS: Rt=2.09 mim, m/z 439.3 (M+H)⁺].

c)1-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-4-yl-4-isopropylpiperazine-1-carboxylate

To a suspension of1-(6-(benzyloxy)pyridin-3-yl)-piperidin-4-yl-4-isopropylpiperazine-1-carboxylate(200 mg, 0.46 mmol) in MeOH (10 mL) was added 10% Pd/C (200 mg) and themixture was hydrogenated (hydrogen balloon) at rt for 10 min. Thecatalyst was removed by filtering through Celite® and the filtrate wasconcentrated under vacuum. The desired product was obtained as a whitesolid after pre-HPLC purification (40 mg, 25%). [¹H NMR (400 MHz,MeOD-d₄) δ 7.50 (dd, J=10 Hz, J₂=3.2 Hz, 1H), 6.81 (d, J=3.2 Hz, 1H),6.41 (d, J=10 Hz, 1H), 4.68 (m, 1H), 3.45 (br, 4H), 3.00 (m, 2H), 2.75(m, 3H), 2.59 (m, 4H), 1.90 (m, 2H), 1.70 (m, 2H), 1.02 (d, J=6.4 Hz,6H); LCMS: Rt=1.37 min, m/z 349.2 (M+H)⁺].

Table 1 shows compounds of formula (I). Examples 1.1 to 1.6 weresynthesized according to Method A; Examples 2.1 to 2.3 were synthesizedaccording to Method B; Example 3.1 was synthesized according to MethodC.

TABLE 1 LCMS Rt [min], Ex. Structure Name method [M + H]⁺ 1.1

1-(6-oxo-1,6-dihydropyridazin-3- yl)piperidin-4-yl 4-cyclobutylpiperazine-1- carboxylate 1.65 (A) 362.2 1.2

1-(1-methyl-6-oxo-1,6- dihydropyridazin-3-yl)piperidin- 4-yl4-isopropylpiperazine-1- carboxylate 1.4 (A) 364.2 1.3

1-(6-oxo-1,6-dihydropyridazin-3- yl)piperidin-4-yl 4-isopropylpiperazine-1- carboxylate 1.33 (A) 350.2 1.4

1-(6-oxo-1,6-dihydropyridazin-3- yl)piperidin-4-yl 4-cyclopropylpiperazine-1- carboxylate 1.05 (A) 348.2 1.5

1-(1-methyl-6-oxo-1,6- dihydropyridazin-3-yl)piperidin- 4-yl4-cyclobutylpiperazine-1- carboxylate 1.44 (A) 376.3 1.6

1-(1-ethyl-6-oxo-1,6- dihydropyridazin-3-yl)piperidin- 4-yl4-isopropylpiperazine-1- carboxylate 0.87 (A) 378.2 2.1

1-(1-methyl-2-oxo-1,2- dihydropyridin-4-yl)piperidin- 4-yl4-isopropylpiperazine-1- carboxylate 1.31 (B) 363.3 2.2

1-(2-oxo-1,2-dihydropyridin-4- yl)piperidin-4-yl 4-cyclobutylpiperazine-1- carboxylate 1.31 (B) 361.2 2.3

1-(2-oxo-1,2-dihydropyridin-4- yl)piperidin-4-yl 4-isopropylpiperazine-1- carboxylate 1.26 (B) 349.2 3.1

1-(6-oxo-1,6-dihydropyridin-3- yl)piperidin-4-yl 4-isopropylpiperazine-1- carboxylate 1.37 (C) 349.2

Biological Testing 1.1 In-Vitro Testing A) Potency Assessment

The potency of compounds of the invention as H3 receptor antagonists canbe assessed by measuring the blockade of(R)-alpha-methylhistamine-mediated cAMP production utilizing a LANCEUltra cAMP kit (PE #TRF0263) in CHO cells expressing human H3 receptors(GenBank: BC096840; Strausberg R L et al, Proc. Natl. Acad. Sci. U.S.A.99(26), 16899-16903; 2002).

Protocol:

1. Preparation of the stimulation buffer (30 ml): 29.4 ml HBSS (GIBCO#14025), 150 μl 1 M HEPES (GIBCO #15630), 30 μl 500 mM IBMX (CALBIOCHEM#410957) and 400 μl 7.5% BSA (GIBCO #10438-026).

2. Preparation of assay plate: Different concentrations of the compoundsof the invention (0.01-1000 nM), H3 positive controls and cAMPcalibration standards; 3 mM Forskolin (CALBIOCHEM #344270); 5 μM(R)-alpha-methylhistamine (H3 receptor agonist); 1% DMSO (SIGMA #D2650);total volume: 95 nl.

3. Preparation of the cell solution: Collect cells with stimulationbuffer, final density: 100,000 cells/ml.

4. Reaction: (a) transfer 10 μl of cell solution to assay plate, (b)centrifuge at 600 rpm for 3 min and incubate 50 min at room temperature,(c) add 5 μL 4× Eu-cAMP tracer solution (60 μl Eu-cAMP tracer stocksolution+2.94 ml cAMP detection buffer) and 5 μL 4× ULight™-anti-cAMPsolution (20 μl Eu-cAMP tracer stock solution+2.98 ml cAMP detectionbuffer) to assay plate.

5. Reading plate on EnVision: flash energy: 100%; excitation filter: 111UV2 320; emission filter: 203 (Eu 615) and 205 (APC 665); number oflaser flashes: 20; window: 100 μs; laser mirror module: 445 or 446;laser cycle: 16,600 μs.

6. Data analysis by GraphPad Prism: log (compound concentration) vs.response; variable slope.

B) Affinity Assessment

The affinity of compounds of the invention to the H3 receptor can beassessed by measuring displacement of binding of the radioligand[3H]-N-α-Methylhistamine (PerkinElmer, #NET1027250UC) to membranescontaining human H3 receptors (PerkinElmer, #ES-392-M400UA; GenBank:NM_(—)007232.2; Hill S J et al, International Union of PharmacologyXIII. Classification of histamine receptors, Pharmacol Rev, 49(3),253-278, 1997).

Protocol:

1. Preparation of binding assay buffer (500 ml): 25 ml 1 M Tris-HCl pH7.5 (Invitrogen, #15567-027), 2.5 ml 1 M MgCl2 (Sigma, #M1028-100 mL),472.5 ml ddH2O.

2. Compound serial dilution: Dilution was performed by BioTek Precisionon compound dilution plate. Compound concentrations start at 5 or 10 μM,10 point dose titrations with 3- or 5-fold serial dilutions.

3. Preparation of 2× membrane solution (25 ml): 1.25 ml human HistamineH3 receptor stock, 23.75 ml assay buffer.

4. Preparation of 2× solution of [3H]-N-α-methylhistamine (25 ml): 4.27μl [3H]-N-α-methylhistamine stock, 25 ml assay buffer.

5. Assemble binding reaction: (a) transfer 1 μl of compound solution, 1μl 100% DMSO and 1 μl 1 M (R)(−)-α-Methylhistamine (Sigma, #H128) to thereaction plate at room temperature, (b) transfer 50 μl of 2× proteinsolution to reaction plate, (c) transfer 49 μl of 2× radioligandsolution to reaction plate (Corning® 96 well EIA/RIA plate; Sigma,#CLS3797).

6. Cover the reaction plate with a TopSeal™-A film (Perkin Elmer,#6005185) and incubate at 28° C. for 120 min. Equilibrate Zeba SpinDesalting Plates (Thermo Scientific, #89808) to room temperature for 120min.

7. Remove the sealing material from the bottom of the filtration plate.Place the plate on a wash plate. Centrifuge at 1000 g for 2 min toremove the storage buffer at room temperature.

8. Transfer 70 μl binding reaction from reaction plate into filtrationplates. Place the filtration plates on top of collection plate.Centrifuge the plate assembly at 1000 g for 2 min to collect the proteinwith bound radioligand. Add 200 μl of Microscint-40 (PerkinElmer,#6013641-1L) to each well of the collection plate. Cover the plates withTopSeal™-A film.

9. Read the plates on Wallac Microbeta Trilux 2450, Instrument settings:counting mode: CPM, counting time: 2 min.

10. Data analysis: GraphPad Prism: log (compound concentration) vs.response; variable slope. The Ki is calculated based on Chang andPrusoff: Ki=IC50/{1+([radioligand]/Kd)}

Table 2 represents Ki values from above described potency/affinityassessments of compounds of the invention against human H3 receptors.

TABLE 2 Potency Affinity Example Ki (nM) Ki (nM) 1.1 1.3 26 1.2 2.4 311.3 1.2 10 1.4 2.3 25 1.5 1.1 25 1.6 2.9 44 2.1 3.1 20 2.2 0.5 25 2.30.9 12 3.1 1.6 1.2

1.2 In-Vivo Testing A) Effects on Brain Tele-Methylhistamine Levels

Compounds of the invention were dissolved in 20%2-hydroxyl-beta-cyclodextran (HBC) and then sonicated briefly untilthere is little or no suspension in the solution. Animals (maleSprague-Dawley rats at the age of 8 weeks) were orally dosed with testcompounds I hour or other longer time points before they were sacrificedusing CO₂.

Blood Sample Collection:

A cardiac puncture was performed to collect blood sample from thecardiac cavity. The collected blood was immediately mixed with EDTA-K220 μl/ml to avoid blood clotting. The blood samples in tubes were thencentrifuged (15 mim, 6000 rpm) and the plasma transferred to new tubesand then temporarily kept in dry ice until they were stored in a −70° C.freezer.

CSF collection: CSF samples were taken from the foramen magnum of theanimal (using a #0.5 intravenous needle), and the CSF sample were keptin dry ice.

Brain Tissue Collection:

The rat brain were taken out of the skull and rinsed with ice-coldsaline first. The frontal cortex was separated from the rest of thebrain on top of a petri dish with ice underneath. The wet weight of thefrontal cortex was weighed and recorded immediately. The frontal cortexsample was then kept in dry ice until they are transferred to a −70° C.freezer.

Bioanalytical Methods for Tele-Methyl Histamine and Compounds:

-   -   Instrument: Agilent 6410, triple quadrupole mass spectrometer    -   Matrix: rat plasma, frontal cortex homogenate and cerebrospinal        fluid (CSF)    -   Analyte: H3 compounds.    -   Internal standard: Dexamethasone

HPLC Conditions Mobile Phase A: H2O—0.1% NH3.H2O:

-   -   Mobile phase B: MeOH-0.1% NH3.H2O    -   Column: Ultimate XB-C18 (2.1×50 mm, 5 μm)    -   Flow rate: 0.45 mL/min, temperature: 40° C.

MS Conditions:

-   -   ESI: positive ion    -   MRM detection    -   Dexamethasone: [M+H]+m/z 393.3→373.2; CE: 4; Fragmentor: 110

Sample Preparation: Frontal Cortex:

the brain sample was homogenized for 2 min with 3 volumes (v/w) ofhomogenizing solution (EtOH:PBS=85:15), and then centrifuged at 12,000rpm for 5 min. The 30 μL supernatant of brain homogenate sample wasadded with 30 μL of the internal standard (Dexamethasone, 300 ng/mL) andthen followed by 150 μL ACN for protein precipitation. The mixture wasvortexed for 2 min and centrifuged at 12000 rpm for 5 min. The 5 μLsupernatant was injected onto LC-MS/MS for analysis.

Plasma and CSF:

an aliquot of 30 μL sample was added with 30 μL of the internal standard(300 ng/mL Dexamethasone) and then followed by 150 μL ACN for proteinprecipitation. The mixture was vortexed for 2 min and centrifuged at12000 rpm for 5 min. The 5 μL supernatant was injected onto LC-MS/MS foranalysis.

Table 3 represents data from measurements of the tele-methylhistaminelevel in brain.

TABLE 3 % change in tele- methylhistamine brain levels Example for 10mg/kg @ 1 h 1.1 72 1.2 138 1.3 115

B) Effects on Wakefulness

Animals: Male Sprague-Dawly rats (280-320 g) were housed individuallyunder an ambient temperature of 22±0.5° C. with a relative humidity of60±2% and an automatically controlled 12-h light/12-h dark cycle (lighton at 07:00, illumination intensity 100 lux). The animals had freeaccess to food and water.

EEG recording set up, Polygraphic Recordings and Vigilance StateAnalysis: Under pentobarbital anesthesia (50 mg/kg, i.p.), rats werechronically implanted with EEG and electromyogram (EMG) electrodes forpolysomnographic recordings (Huang et al, J Neurosci, 23, 5975-5983,2003). Two stainless steel screws (1 mm in diameter) EEG electrodes (thefirst screw: anteroposterior (AP), +2 mm; left-right (LR), −2 mm; andthe second: AP, −2 mm; LR, −2 mm, AP from bregma, LR from lambda) and areference electrode (opposite to EEG screw side, AP, +3 mm; LR, 3 mm)were surgically implanted and 3 stainless steel screws for anchorage tothe skull. Two insulated stainless steel, Teflon-coated wires werebilaterally placed into both trapezius muscles and served as EMGelectrodes for rats. All electrodes were attached to a micro connectorand fixed to the skull with dental cement.

The EEG and EMG recordings were carried out by means of a slip ringdesigned so that behavioral movement of the rat would not be restricted.After an 8-day recovery period, the rats were housed individually intransparent barrels and habituated to the recording cable for 3-4 daysbefore polygraphic recording.

For the study of spontaneous sleep-wakefulness cycles, each animal wasrecorded for 24 h beginning at 19:00 P.M., the offset of the lightperiod. The animals then entered the pharmacological phase of the study,in which sleep-wakefulness parameters were recorded for 72 h. The datacollected during the first 24 h also served as baseline comparison datafor the second experimental day.

Cortical EEG and EMG signals were amplified, filtered (EEG, 0.5-30 Hz;EMG, 20-200 Hz), digitized at a sampling rate of 128 Hz, and recorded byusing SLEEPSIGN (Kissei Comtec, Nagano, Japan). When complete,polygraphic recordings were automatically scored offline by 4-sec epochsas wake, REM, and NREM sleep by SleepSign according to standard criteria(Huang et al, Nat Neurosci, 8, 858-859, 2005). As a final step, definedsleep-wake stages were examined visually and corrected, if necessary.EEG power density curve was plotted for each stage during 4 h after drugadministration. The power of each 0.25 Hz bin was averaged across thesleep or wake stage and normalized as a group by calculating thepercentage of each bin from the total power (0.25-25 Hz).

Pharmacological Treatments Tested compounds, caffeine (positivereference compound) or compounds of the invention were prepared in 20%2-hydroxyl-beta-cyclodextran (HBC). On the vehicle-treated day, allanimals were administered with vehicle at 9:00 A.M. On the drug-treatedday, the test compound, caffeine, or vehicle was given at 9:00 A.M.Thereafter, continuous recording was kept to the 3rd day. The volume wasinjected oral, or intraperitoneally at 2 ml/kg. Separate groups of ratswere used for each dose (n=8 rats per group).

Time-course changes in the amounts of sleep-wake, sleep/wake stagetransition number, as well as number and duration of sleep/wake bouts inlight/dark phases, were analyzed by the paired t test, with each animalserving as its own control.

Table 4 represents data from measurements of percent increase inwakefulness in rats. Date is given for first 4 hours after oral compoundadministration.

TABLE 4 % increase in wakefulness Example at 10 mg 1.1 42.1 1.2 48.8 1.319.1 *p < 0.5, **p < 0.01 (comparison with vehicle group)

In one embodiment, the invention provides a method of inhibiting H3receptors in a subject, wherein the method comprises administering tothe subject a therapeutically effective amount of a compound of formulaI or a pharmaceutically acceptable salt thereof.

In a further embodiment, the invention provides a method of treating adisorder or a disease in a subject mediated by H3 receptors, wherein themethod comprises administering to the subject a therapeuticallyeffective amount of a compound of formula I or a pharmaceuticallyacceptable salt thereof. Preferably said disorder or said disease isselected from narcolepsy; fatigue associated with multiple sclerosis;fatigue associated with Parkinson's disease; cognitive impairmentassociated with schizophrenia; cognitive impairment associated withAlzheimer's disease; mild cognitive impairment; Tourette syndrome; andAttention-deficit hyperactivity disorder; very especially narcolepsy.

In yet a further embodiment, the invention provides the use of acompound of formula I or a pharmaceutically acceptable salt thereof, forthe treatment of a disorder or disease in a subject mediated by H3receptors.

In yet a further embodiment, the invention provides the use of acompound of formula I or a pharmaceutically acceptable salt thereof, forthe treatment of a disorder or disease in a subject characterized by anabnormal activity of H3 receptors. Preferably said disorder or saiddisease is selected from narcolepsy; fatigue associated with multiplesclerosis; fatigue associated with Parkinson's disease; cognitiveimpairment associated with schizophrenia; cognitive impairmentassociated with Alzheimer's disease; mild cognitive impairment; Tourettesyndrome; and Attention-deficit hyperactivity disorder; very especiallynarcolepsy.

In yet a further embodiment, the invention provides the use of acompound of formula I or a pharmaceutically acceptable salt thereof, forthe treatment of a disorder or disease in a subject associated withirregularities of H3 receptor-modulated signal transmission. Preferablysaid disorder or said disease is selected from narcolepsy; fatigueassociated with multiple sclerosis; fatigue associated with Parkinson'sdisease; cognitive impairment associated with schizophrenia; cognitiveimpairment associated with Alzheimer's disease; mild cognitiveimpairment; Tourette syndrome; and Attention-deficit hyperactivitydisorder; very especially narcolepsy.

II. Solid Forms of Carbamate Derivatives

The present invention also relates to solid forms of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate and to pharmaceutical compositionscomprising them, and to their use as medicaments.

The compound I-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate of the formula IA

is described hereinbefore.

Selection criteria for solid forms depend on the planned indications androute(s) of administration. For a CNS-indication, such as narcolepsy,with an envisaged oral route of administration it is important to e.g.achieve a good absorption/oral bioavailability. Especially suitablesolid forms are crystalline forms having a low hygroscopy, a highaqueous solubility, a high melting point and do not exist in multipleforms (e.g. polymorphs, solvates and/or hydrates). Further relevantparameters are safety aspects (e.g. low toxicity), stability in bulk,compatibility with excipients, pH of aqueous solution, good morphologyand easy handling.

The invention provides the free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in solid form. The inventionfurther provides a salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in solid form, wherein said salt isthe citrate, hydrochloride, fumarate, adipate, maleate or sebacate of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate. Unless specified otherwise, saidfree form or said salt together will be referred to hereinafter as“SOLID FORM OF THE INVENTION”.

As used herein “solid form” may include hydrates and solvates.

As used herein “crystalline form” refers to a solid form of a molecule,atom and/or ion, in which its constituent atoms, molecules and/or ionsare arranged in an orderly repeating pattern extending in all threespatial dimensions.

As used herein “polymorph” refers to crystalline forms having the samechemical composition but different spatial arrangements of themolecules, atoms and/or ions forming the crystal.

As used herein “amorphous form” refers to a solid form of a molecule,atom and/or ion that is not crystalline. An amorphous solid does notdisplay a definitive X-ray diffraction pattern.

As used herein “solvate” refers to a form, e.g. a crystalline form, of amolecule, atom and/or ions that further comprises molecules of a solventor solvents incorporated into the solid structure, e.g. crystallinelattice structure. The solvent molecules in the solvate may be presentin a regular arrangement and/or a non-ordered arrangement. The solvatemay comprise either a stoichiometric or nonstoichiometric amount of thesolvent molecules. For example, a solvate with a nonstoichiometricamount of solvent molecules may result from partial loss of solvent formthe solvate. Solvates may occur as dimers or oligomers comprising morethan one molecule of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate within a crystalline latticestructure.

As used herein “substantially pure”, when used in reference to a solidform, means a compound, e.g. a salt (such as the citrate of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate), having a purity greater than 90weight %, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and99 weight %, and also including equal to about 100 weight % of thecompound, e.g. of the citrate of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate, based on the weight of the solidform. The remaining material in the solid form may comprise e.g.reaction impurities and/or processing impurities arising from itspreparation and/or—if applicable—other form(s) of the compound. Forexample, a crystalline form of the citrate of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate may be deemed substantially pure inthat it has a purity greater than 90 weight %, as measured by means thatare at this time known and generally accepted in the art, where theremaining less than 10 weight % of material comprises reactionimpurities and/or processing impurities.

As used herein “mono-” in connection with acids refers to a base to acidratio of about 1:1.

As used herein “sesqui-” in connection with acids refers to a base toacid ratio of about 1:1.5.

As used herein “di-” in connection with acids refers to a base to acidratio of about 1:2.

The term “substantially the same” with reference to X-ray diffractionpeak positions means that typical peak position and intensityvariability are taken into account. For example, one skilled in the artwill appreciate that the peak positions (2Θ) will show someinter-apparatus variability, typically as much as 0.2°. Further, oneskilled in the art will appreciate that peak intensities will showinter-apparatus variability as well as variability due to degree ofcrystallinity, preferred orientation, prepared sample surface, and otherfactors known to those skilled in the art, and should be taken asqualitative measure only.

1. Free Form

In one embodiment, the SOLID FORM OF THE INVENTION is the free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate, e.g. in crystalline form.

1.1. First Embodiment of Free Form:

A free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form (Form A of thefree form) may be produced from cooling crystallization of asupersaturated solution of the compound in ethyl acetate atconcentrations of about 100 mg/ml. The clear point (temperature at whichthe compound will dissolve) is about 35° C. The cloud point (temperatureat which the compound will crystallize) is about 4° C. The XRPD patternof a sample prepared according to such a method (see also ExampleII.1.1) is shown in FIG. 1A. Measurements were performed at atemperature of about 22° C. and an x-ray wavelength, λ, of 1.5418 Å(CuKα λ=1.5418 Å).

Summary of XRPD Pattern:

2 theta Intensity No. (deg°) (cts) 1 4.9 5305 2 9.7 2288 3 14.5 726 414.6 564 5 15.4 9230 6 16.0 3079 7 16.9 3327 8 17.3 1215 9 18.1 1995 1019.5 2862 11 20.5 13826 12 20.8 8027 13 21.3 2578 14 21.4 2373 15 22.9535 16 24.4 7248 17 24.8 918 18 26.0 400 19 26.8 799 20 28.8 460 21 29.41197 22 31.0 699 23 35.5 355 24 39.5 352

In one embodiment, Form A of the free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form ischaracterized by an XRPD pattern with at least four, more preferablyfive, most preferably all of the following peaks at an angle ofrefraction 2 theta (20) of 4.9, 15.4, 16.9, 20.5, 20.8 and 24.4, ±0.2,respectively.

In one embodiment, Form A of the free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form ischaracterized by an XRPD pattern substantially the same as the XRPDpattern shown in FIG. 1A.

Form A of the free from shows good solubility in aqueous media across apH range from about 1-8. Its melting point was determined by heating at10° C./minute to be about 123° C.

1.2. Second Embodiment of Free Form:

A free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form (Form B of thefree form) was found as described in the Examples section (see ExampleII.1.2). The associated XRPD pattern is shown in FIG. 1B.

Summary of XRPD Pattern:

2 theta Intensity No. (deg°) (cts) 1 9.4 386 2 11.3 2380 3 13.6 348 415.0 2422 5 16.0 481 6 16.7 2577 7 17.4 1391 8 18.3 738 9 18.6 802 1019.4 7589 11 20.8 1401 12 21.7 454 13 22.7 2907 14 23.2 7040 15 24.0 30616 24.6 1591 17 27.7 10625 18 27.8 5756 19 28.1 712 20 28.7 1879 21 29.5674 22 29.9 1086 23 31.6 637 24 32.5 1248 25 32.7 910 26 33.5 724 2733.6 954 28 34.3 623 29 35.1 359 30 35.6 358 31 36.1 992 32 37.0 457 3337.7 333 34 39.2 330

In one embodiment, Form B of the free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form ischaracterized by an XRPD pattern with at least four, more preferablyfive, most preferably all of the following peaks at an angle ofrefraction 2 theta (20) of 9.4, 11.3, 13.6, 15.0, 16.0, 16.7, 17.4,18.3, 18.6, 19.4, 20.8, 21.7, 22.7, 23.2, 24.0, 24.6, 27.7, 27.8, 28.1,28.7, 29.5, 29.9, 31.6, 32.5, 32.7, 33.5, 33.6, 34.3, 35.1, 35.6, 36.1,37.0, 37.7, and 39.2, ±0.2, respectively.

In one embodiment, Form B of the free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form ischaracterized by an XRPD pattern with at least four, more preferablyfive, most preferably all of the following peaks at an angle ofrefraction 2 theta (20) of 9.4, 19.4, 22.7, 23.2, 27.7 and 27.8, ±0.2,respectively.

In one embodiment, Form B of the free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form ischaracterized by an XRPD pattern substantially the same as the XRPDpattern shown in FIG. 1B.

Form B of the free from shows good solubility in aqueous media. Itsmelting point was determined by heating at 10° C./minute to be about124° C. (onset).

Salts 2. Citrate Salt:

In one embodiment, the SOLID FORM OF THE INVENTION is the citrate saltof 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate, e.g. in crystalline form.

2.1. First Embodiment of Citrate Salt:

A citrate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form (Form A of thecitrate salt) may be produced from acetone/diethylether when twoequivalents citric acid are used.

It shows good solubility in aqueous media. Its melting point wasdetermined by heating at 10° C./minute to be about 141.2° C.

The X-ray powder diffraction (XRPD) pattern of a sample preparedaccording to this method (see also Example II.2.1) is shown in FIG. 2A.Measurements were performed at a temperature of about 22° C. and anx-ray wavelength, λ, of 1.5418 Å (CuKα λ=1.5418 Å).

Summary of XRPD Pattern:

2 theta No. No. (deg°) Intensity 1 19.4 130 2 24.0 130 3 14.0 128 4 16.6128 5 17.5 128 6 17.3 122 7 12.0 118 8 20.8 110 9 25.6 108 10 16.1 10311 22.5 103 12 18.2 99 13 20.1 97 14 10.2 93 15 31.3 82 16 8.4 60 17 5.557

In one embodiment, Form A of the citrate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form ischaracterized by an XRPD pattern with at least four, more preferablyfive, most preferably all of the following peaks at an angle ofrefraction 2 theta (20) of 14.0, 16.6, 17.3, 17.5, 19.4 and 24.0±0.2,respectively.

In one embodiment, Form A of the citrate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form ischaracterized by an XRPD pattern substantially the same as the XRPDpattern shown in FIG. 2A.

Analysis of the proton-NMR spectrum for the salt of Example II.2.1 (seeFIG. 2B) demonstrated a base/acid ratio of about 1:1.5.

In one embodiment, the SOLID FORM OF THE INVENTION is the sesqui-citratesalt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate.

In one embodiment, the SOLID FORM OF THE INVENTION is the sesqui-citratesalt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form.

2.2. Second Embodiment of Citrate Salt:

A citrate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form (Form B of thecitrate salt) may be produced from acetone when one equivalent citricacid is used.

It shows good solubility in aqueous media. Its melting point wasdetermined by heating at 10° C./minute to be about 172° C.

The X-ray powder diffraction (XRPD) pattern of a sample preparedaccording to this method (see also Example II.2.2) is shown in FIG. 2C.The sample contained about 1.5% of residual acetone. Measurements wereperformed at a temperature of about 22° C. and an x-ray wavelength, λ,of 1.5418 Å (CuKα λ=1.5418 Å).

Summary of XRPD Pattern:

2 theta Intensity No. (deg°) (cts) 1 3.2 406 2 5.8 54 3 9.3 1460 4 10.8321 5 12.0 1561 6 12.7 134 7 14.1 110 8 15.1 204 9 16.3 811 10 16.4 77211 17.3 1164 12 18.3 437 13 18.6 406 14 19.3 425 15 20.7 469 16 22.0 9717 23.3 271 18 23.9 308 19 25.9 138 20 26.7 98 21 27.9 38 22 31.0 27 2331.7 35 24 32.5 50 25 34.9 60 26 37.2 65

In one embodiment, Form B of the citrate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form ischaracterized by an XRPD pattern with at least four, more preferablyfive, most preferably all of the following peaks at an angle ofrefraction 2 theta (20) of 3.2, 9.3, 10.8, 12.0, 15.1, 16.3, 16.4, 17.3,18.3, 18.6, 19.3, 20.7, 23.3, and 23.9, ±0.2, respectively.

In one embodiment, Form B of the citrate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form ischaracterized by an XRPD pattern substantially the same as the XRPDpattern shown in FIG. 2C.

3. Hydrochloride Salt:

In one embodiment, the SOLID FORM OF THE INVENTION is the hydrochloridesalt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate, e.g. in crystalline form.

4.1. First Embodiment of Hydrochloride Salt:

A hydrochloride salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form (Form A ofhydrochloride salt) may be produced from acetone when one equivalenthydrochloric acid is used.

It shows good solubility in aqueous media. Its melting point wasdetermined by heating at 10° C./minute to be 249.8° C. (onset) withsubsequent decomposition.

The XRPD pattern of a sample prepared according to this method (see alsoExample II.3.1) is shown in FIG. 3A. Measurements were performed at atemperature of about 22° C. and an x-ray wavelength, λ, of 1.5418 Å(CuKα λ=1.5418 Å).

Summary of XRPD Pattern:

2 theta No. (deg°) Intensity 1 16.4 287 2 24.8 215 3 27.5 153 4 20.2 1195 29.7 103 6 17.2 96 7 27.0 94 8 22.0 91 9 19.0 82 10 23.9 81 11 10.9 7712 36.4 68 13 39.0 66 14 14.0 59 15 31.2 56 16 43.6 38 17 40.5 37

In one embodiment, Form A of the hydrochloride salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form ischaracterized by an XRPD pattern with at least four, more preferablyfive, most preferably all of the following peaks at an angle ofrefraction 2 theta (20) of 16.4, 17.2, 20.2, 24.2, 27.5 and 29.7±0.2,respectively.

In one embodiment, Form A of the hydrochloride salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form ischaracterized by an XRPD pattern substantially the same as the XRPDpattern shown in FIG. 3A.

4.2. Second Embodiment of Hydrochloride Salt:

An anhydrous hydrochloride salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form (Form B ofhydrochloride salt) may be produced from acetone when two equivalentshydrochloric acid are used.

It shows good solubility in aqueous media. Its melting point, for asample stored at 40° C. and 75% relative humidity for 7 days, wasdetermined by heating at 10° C./minute to be about 250° C. (onset).

The X-ray powder diffraction (XRPD) pattern of a sample preparedaccording to this method (see also Example II.3.2) is shown in FIG. 3B.Measurements were performed at a temperature of about 22° C. and anx-ray wavelength, λ, of 1.5418 Å (CuKα λ=1.5418 Å).

Summary of XRPD Pattern:

2 theta Intensity No. (deg°) (cts) 1 5.7 98 2 9.1 76 3 10.0 603 4 10.7521 5 11.9 463 6 13.3 418 7 13.7 163 8 15.4 191 9 15.9 970 10 16.5 22511 16.8 127 12 17.1 135 13 18.3 494 14 18.7 443 15 19.5 439 16 20.0 8017 20.7 82 18 22.9 36 19 23.6 323 20 24.2 136 21 25.0 595 22 25.4 137 2326.9 1100 24 27.0 966 25 27.7 296 26 29.4 198 27 30.1 67 28 31.9 51 2932.7 63 30 34.2 20 31 35.9 30 32 38.1 22

In one embodiment, Form B of the hydrochloride salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form ischaracterized by an XRPD pattern with at least four, more preferablyfive, most preferably all of the following peaks at an angle ofrefraction 2 theta (20) of 5.7, 9.1, 10.0, 10.7, 11.9, 13.3, 13.7, 15.4,15.9, 16.5, 16.8, 17.1, 18.3, 18.7, 19.5, 20.0, 20.7, 23.6, 24.2, 25.0,25.4, 26.9, 27.0, 27.7, 29.4, 30.1, 31.9, and 32.7, ±0.2, respectively.

In one embodiment, Form B of the hydrochloride salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form ischaracterized by an XRPD pattern substantially the same as the XRPDpattern shown in FIG. 3B.

4. Fumarate Salt:

In one embodiment, the SOLID FORM OF THE INVENTION is the fumarate saltof 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate, e.g. in crystalline form.

3.1. First Embodiment of Fumarate Salt:

An anhydrous fumarate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form (Form A offumarate salt) may be produced from methanol/acetone as described inExample 4.1 when one equivalent fumaric acid is used.

It shows good solubility in aqueous media. Its melting point wasdetermined by heating at 10° C./minute to be about 156° C.

The X-ray powder diffraction (XRPD) pattern of a sample preparedaccording to this method (see also Example II.4.1) is shown in FIG. 4A.Measurements were performed at a temperature of about 22° C. and anx-ray wavelength, λ, of 1.5418 Å (CuKα λ=1.5418 Å).

Summary of XRPD Pattern:

2 theta Intensity No. (deg°) (cts) 1 6.5 662 2 10.1 1209 3 10.7 813 412.4 156 5 13.0 3669 6 13.9 661 7 16.0 90 8 16.7 1428 9 16.8 1725 1017.2 2712 11 17.7 290 12 18.8 209 13 20.2 1475 14 20.5 631 15 21.6 151816 21.9 1748 17 22.1 1795 18 23.1 237 19 23.4 100 20 25.0 1464 21 25.11002 22 25.4 603 23 26.4 114 24 27.5 297 25 28.0 790 26 28.8 293 27 29.9255 28 32.8 149 29 33.2 174 30 33.7 80 31 38.3 73

In one embodiment, Form A of the fumarate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form ischaracterized by an XRPD pattern with at least four, more preferablyfive, most preferably all of the following peaks at an angle ofrefraction 2 theta (20) of 6.5, 10.1, 10.7, 12.4, 13.0, 13.9, 16.7,16.8, 17.2, 17.7, 18.8, 20.2, 20.5, 21.6, 21.9, 22.1, 23.1, 23.4, 25.0,25.1, 25.4, 26.4, 27.5, 28.0, 28.8, 29.9, 32.8, and 33.2, ±0.2,respectively.

In one embodiment, Form A of the fumarate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form ischaracterized by an XRPD pattern substantially the same as the XRPDpattern shown in FIG. 4A.

3.2. Second Embodiment of Fumarate Salt:

An anhydrous fumarate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form (Form B offumarate salt) may be produced from methanol/acetone as described inExample 4.2 when two equivalents fumaric acid are used.

It shows good solubility in aqueous media. Its melting point wasdetermined by heating at 10° C./minute to be about 155° C.

The X-ray powder diffraction (XRPD) pattern of a sample preparedaccording to this method (see also Example II.4.2) is shown in FIG. 4B.Measurements were performed at a temperature of about 22° C. and anx-ray wavelength, λ, of 1.5418 Å (CuKα λ=1.5418 Å).

Summary of XRPD Pattern:

2 theta Intensity No. (deg°) (cts) 1 6.4 549 2 7.8 112 3 8.7 462 4 10.6232 5 11.3 215 6 11.8 742 7 12.9 523 8 13.1 178 9 13.8 1953 10 14.0 172711 15.2 176 12 15.7 1780 13 16.2 736 14 16.6 1901 15 16.9 335 16 18.3110 17 18.7 954 18 18.8 689 19 19.1 2404 20 19.3 562 21 19.7 318 22 20.1146 23 20.5 323 24 21.0 1741 25 21.4 840 26 21.9 2681 27 22.8 669 2823.8 364 29 24.0 1027 30 24.4 317 31 24.7 524 32 25.2 935 33 25.6 448 3426.0 566 35 26.1 699 36 27.8 528 37 28.3 123 38 29.1 220 39 29.5 353 4030.6 201 41 31.4 256 42 31.7 142 43 32.1 318 44 32.7 308 45 34.7 98 4635.3 194 47 37.4 154 48 38.2 168

In one embodiment, Form B of the fumarate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form ischaracterized by an XRPD pattern with at least four, more preferablyfive, most preferably all of the following peaks at an angle ofrefraction 2 theta (20) of 6.4, 8.7, 10.6, 11.3, 11.8, 12.9, 13.8, 14.0,15.7, 16.2, 16.6, 16.9, 18.7, 18.8, 19.1, 19.3, 19.7, 20.5, 21.0, 21.4,21.9, 22.8, 23.8, 24.0, 24.4, 24.7, 25.2, 25.6, 26.0, 26.1, 27.8, 29.1,29.5, 30.6, 31.4, 32.1, 32.7, and 35.3, ±0.2, respectively.

In one embodiment, Form B of the fumarate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form ischaracterized by an XRPD pattern substantially the same as the XRPDpattern shown in FIG. 4B.

Preparation Methods for Crystalline Forms

Crystalline forms may be prepared by a variety of methods, including forexample, crystallization or recrystallization from a suitable solvent,sublimation, growth from a melt, solid state transformation from anotherphase, crystallization from a supercritical fluid, and jet spraying.Techniques for crystallization or recrystallization of crystalline formsfrom a solvent mixture include, for example, evaporation of the solvent,decreasing the temperature of the solvent mixture, crystal seeding asupersaturated solvent mixture of the molecule and/or salt, freezedrying the solvent mixture, and addition of antisolvents(countersolvents) to the solvent mixture. High throughputcrystallization techniques may be employed to prepare crystalline formsincluding polymorphs.

Crystals of drugs, including polymorphs, methods of preparation, andcharacterization of drug crystals are discussed in Solid-State Chemistryof Drugs, S. R. Byrn, R. R. Pfeiffer, and J. G. Stowell, 2^(nd) Edition,SSCI, West Lafayette, Ind. (1999).

For crystallization techniques that employ solvent, the choice ofsolvent or solvents is typically dependent upon one or more factors,such as solubility of the compound, crystallization technique, and vaporpressure of the solvent. Combinations of solvents may be employed, forexample, the compound may be solubilized into a first solvent to afforda solution, followed by the addition of an antisolvent to decrease thesolubility of the compound in the solution and to afford the formationof crystals. An antisolvent is a solvent in which the compound has lowsolubility.

In one method to prepare crystals, a compound is suspended and/orstirred in a suitable solvent to afford a slurry, which may be heated topromote dissolution. The term “slurry”, as used herein, means asaturated solution of the compound, which may also contain an additionalamount of the compound to afford a heterogeneous mixture of the compoundand a solvent at a given temperature.

Seed crystals may be added to any crystallization mixture to promotecrystallization (see “Programmed Cooling of Batch Crystallizers,” ° J.W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26,369-377). In general, seed crystals of small size are used. Seedcrystals of small size may be generated by sieving, milling, ormicronizing of large crystals, or by micro-crystallization of solutions.Care should be taken that milling or micronizing of crystals does notresult in any change in crystallinity form the desired crystal form(i.e., change to amorphous or to another polymorph).

A cooled crystallization mixture may be filtered under vacuum, and theisolated solids may be washed with a suitable solvent, such as coldrecrystallization solvent, and dried under a nitrogen purge to affordthe desired crystalline form. The isolated solids may be analyzed by asuitable spectroscopic or analytical technique, such as solid statenuclear magnetic resonance, differential scanning calorimetry, x-raypowder diffraction, or the like, to assure formation of the preferredcrystalline form of the product. The resulting crystalline form istypically produced in an amount of greater than about 70 weight %isolated yield, preferably greater than 90 weight % isolated yield,based on the weight of the compound originally employed in thecrystallization procedure. The product may be delumped by sieving orforced sieving, if necessary.

Crystalline forms may be prepared directly from the reaction medium ofthe final process for preparing1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate or a SOLID FORM OF THE INVENTION.This may be achieved, for example, by employing in the final processstep a solvent or a mixture of solvents from which the SOLID FORM OF THEINVENTION may be crystallized. Alternatively, crystalline forms may beobtained by distillation or solvent addition techniques. Suitablesolvents for this purpose include, for example, nonpolar solvents andpolar solvents, including protic polar solvents such as alcohols, andaprotic polar solvents such as ketones.

The presence of more than one polymorph in a sample may be determined bytechniques such as powder x-ray diffraction (PXRD) or solid statenuclear magnetic resonance spectroscopy. For example, the presence ofextra peaks in the comparison of an experimentally measured PXRD patternwith a simulated PXRD pattern may indicate more than one polymorph inthe sample. The simulated PXRD may be calculated from single crystalx-ray data; see Smith, D. K., “A FORTRAN Program for Calculating X-RayPowder Diffraction Patterns,” Lawrence Radiation Laboratory, Livermore,Calif., UCRL-7196 (April 1963).

One embodiment of the invention is a method of preparing a citrate saltof 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form comprising thesteps of

(a) preparing a solution of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate and citric acid in acetone, whereinthe 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate:citric acid ratio is about 1:2;(b) adding to the solution of step (a) an ether antisolvent, e.g.diethyl ether, until an acetone:ether antisolvent volume ratio from 1:1to 1:5, e.g. about 1:3, is reached; and(e) isolate the solids by filtration to obtain the citrate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form.

One embodiment of the invention is a method of preparing a hydrochloridesalt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form comprising thesteps of

(a) preparing a solution of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in acetone;(b) adding to the solution of step (a) hydrochloric acid until a1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate:hydrochloric acid ratio of about1:1 is reached; and(e) isolate the solids by filtration to obtain the hydrochloride salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form.

Analysis of Solid Forms

The solid form of a SOLID FORM OF THE INVENTION may be characterizedusing various techniques, the operation of which are well known to thoseof ordinary skill in the art.

The forms may be characterized and distinguished using single crystalx-ray diffraction, which is based on unit cell measurements of a singlecrystal of the form at a fixed analytical temperature. A detaileddescription of unit cells is provided in Stout & Jensen, X-Ray StructureDetermination: A Practical Guide, Macmillan Co., New York (1968),Chapter 3. Alternatively, the unique arrangement of atoms in spatialrelation within the crystalline lattice may be characterized accordingto the observed fractional atomic coordinates. Another means ofcharacterizing the crystalline structure is by powder x-ray diffractionanalysis in which the diffraction profile is compared to a simulatedprofile representing pure powder material, both run at the sameanalytical temperature, and measurements for the subject formcharacterized as a series of 28 values (usually four or more).

Other means of characterizing the form may be used, such as solid statenuclear magnetic resonance (NMR), differential scanning calorimetry,thermography and gross examination of the crystalline or amorphousmorphology. These parameters may also be used in combination tocharacterize the subject form.

Further Aspects

The invention also relates to a SOLID FORM OF THE INVENTION (e.g. Form Aof the free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form) for use as amedicament.

In another embodiment, the invention relates to a SOLID FORM OF THEINVENTION (e.g. Form A of the free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form) for thetreatment of a disorder or disease in a subject mediated by H3receptors. Preferably said disorder or said disease is selected fromnarcolepsy; fatigue associated with multiple sclerosis; fatigueassociated with Parkinson's disease; cognitive impairment associatedwith schizophrenia; cognitive impairment associated with Alzheimer'sdisease; mild cognitive impairment; Tourette syndrome; andAttention-deficit hyperactivity disorder; very especially narcolepsy.

In another embodiment, the invention also relates to the use of a SOLIDFORM OF THE INVENTION (e.g. Form A of the free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form) for themanufacture of a medicament for the prevention, treatment and/or delayof progression of a disorder or disease in a subject mediated by H3receptors. Preferably said disorder or said disease is selected fromnarcolepsy; fatigue associated with multiple sclerosis; fatigueassociated with Parkinson's disease; cognitive impairment associatedwith schizophrenia; cognitive impairment associated with Alzheimer'sdisease; mild cognitive impairment; Tourette syndrome; andAttention-deficit hyperactivity disorder; very especially narcolepsy.

In another embodiment, the invention also relates to the use of a SOLIDFORM OF THE INVENTION (e.g. Form A of the free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form) for theprevention, treatment and/or delay of progression of a disorder ordisease in a subject mediated by H3 receptors. Preferably said disorderor said disease is selected from narcolepsy; fatigue associated withmultiple sclerosis; fatigue associated with Parkinson's disease;cognitive impairment associated with schizophrenia; cognitive impairmentassociated with Alzheimer's disease; mild cognitive impairment; Tourettesyndrome; and Attention-deficit hyperactivity disorder; very especiallynarcolepsy.

In another embodiment, the invention also relates to a method for theprevention, treatment and/or delay of progression of a disorder ordisease in a subject mediated by H3 receptors, in a subject in need ofsuch treatment, which comprises administering to such subject atherapeutically effective amount of a SOLID FORM OF THE INVENTION (e.g.Form A of the free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form). Preferablysaid disorder or said disease is selected from narcolepsy; fatigueassociated with multiple sclerosis; fatigue associated with Parkinson'sdisease; cognitive impairment associated with schizophrenia; cognitiveimpairment associated with Alzheimer's disease; mild cognitiveimpairment; Tourette syndrome; and Attention-deficit hyperactivitydisorder; very especially narcolepsy.

In another embodiment, the invention relates to a method for theprevention, treatment and/or delay of progression of a disorder ordisease in a subject mediated by H3 receptors, in a subject in needthereof, which comprises (i) diagnosing said disorder or disease in saidsubject and (ii) administering to said subject a therapeuticallyeffective amount of a SOLID FORM OF THE INVENTION (e.g. Form A of thefree form of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form). Preferablysaid disorder or said disease is selected from narcolepsy; fatigueassociated with multiple sclerosis; fatigue associated with Parkinson'sdisease; cognitive impairment associated with schizophrenia; cognitiveimpairment associated with Alzheimer's disease; mild cognitiveimpairment; Tourette syndrome; and Attention-deficit hyperactivitydisorder; very especially narcolepsy.

Amorphous forms/crystalline forms of SOLID FORMS OF THE INVENTION areuseful as intermediates for preparing crystalline forms/othercrystalline forms of SOLID FORMS OF THE INVENTION that are useful in thetreatment of the above diseases/conditions.

SOLID FORMS OF THE INVENTION may be used alone or in combination, orformulated with one or more excipients and/or other activepharmaceutical ingredients to provide formulations, as described above,suitable for the treatment of the above diseases/conditions.

The invention therefore also relates to a pharmaceutical compositioncomprising a SOLID FORM OF THE INVENTION as active ingredient and atleast one pharmaceutically acceptable carrier.

Abbreviations:

DSC Differential scanning calorimetryEGA evolved gas analysisTGA thermo gravimetric analysisXRPD X-ray powder diffraction

Example II.1.1 Preparation of free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form

Free form of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate was dissolved in ethyl acetate at aconcentration of 100 mg/ml under heating to its clear point of 35° C.Cooling to its cloud point of 4° C. yielded a crystalline product. Theproduct was analyzed by XRPD (see FIG. 1A).

Example II.1.2 Preparation of free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form

In a vial, equipped with a magnetic stirring bar, 1 equivalent of eachbase listed in the table below was dissolved in 3 ml water. To thissolution, 50 mg Form A of the free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate were added together with 2 mlmethanol. The mixture was stirred at room temperature until a clearsolution was obtained. Then, the stirring bar was removed and thesolution was left to evaporate at room temperature. After 17-24 days(see table below), a crystalline product was obtained. The evaporationtime and the amount of product obtained are listed below:

Base Amount of product Evaporation time L-Lysine 19 mg 17 days N-MethylGlucamine 26 mg 24 days L-Arginine 23 mg 18 days Sodium Hydroxide  5 mg20 days Potassium Hydroxide  7 mg 24 days Magnesium Hydroxide  8 mg 18days Calcium Hydroxide 10 mg 24 days

Precipitates were collected and analyzed by XRPD. A typical XRPDspectrum is depicted in FIG. 1B.

Example II.2.1 Preparation of citrate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form

2 g free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate was dissolved in acetone (5 ml)under stirring at room temperature, and 2.04 g (2 equivalents) of citricacid was also dissolved in acetone (5 ml) in the same condition. In a100 ml crystallizer, equipped with a magnetic stirring bar andcondenser, two solutions were added and stirred. After half an hour, 30ml diethyl ether was added into crystallizer. The slurry was filtered,and the light yellow solid was dried under vacuum at 40° C. for 24 hours(yield: 82.28%). The product was analyzed by XRPD (see FIG. 2A) andproton-NMR (see FIG. 2B). Analysis of the proton-NMR spectrumdemonstrated a base/acid ratio of about 1:1.5.

Example II.2.2 Preparation of citrate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form

25.58 mg of citric acid was dissolved in 3 ml acetone under stirringuntil complete dissolution. 50 mg free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate was added to the solution and themixture was stirred at room temperature for 24 hours. The precipitatewas collected by vacuum filtration, washed with diethyl ether, driedunder vacuum at 50° C. for 14 hours and analyzed by XRPD (see FIG. 2B),TGA/EGA and DSC.

Example II.3.1 Preparation of hydrochloride salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form

In a 100 ml crystallizer, equipped with a magnetic stirring bar andcondenser, 2 g free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate was dissolved in acetone understirring. At room temperature 438 μl (1 equivalent) of hydrochloric acidwas added drop wise. A slight yellow precipitate was immediately formed,and the mixture was stirred at room temperature for 3 hours. The solidwas filtered, dried under vacuum at 40° C. for 24 hours (yield: 81.5%)and analyzed by XRPD (see FIG. 3A).

Example II.3.2 Preparation of hydrochloride salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form

50 mg of free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate was dissolved in 3 ml acetone. Atroom temperature, 22 μl of 37% hydrochloric acid was added and themixture was stirred at room temperature for 24 hours. The precipitatewas recovered under vacuum, washed with diethyl ether, dried undervacuum at 50° C. for 24 hours, and analyzed by XRPD (see FIG. 3B),TGA/EGA and DSC.

Example II.4.1 Preparation of fumarate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form

15.46 mg of fumaric acid was dissolved in 1 ml methanol under stirringuntil complete dissolution. 50 mg free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate was added to the solution and themixture was stirred at room temperature until complete dissolution. Thesolvents were evaporated at room temperature for 48 hours and a yellowoil was obtained. 1 ml acetone was added and the mixture stirred at roomtemperature for 2 hours. A yellow precipitate was recovered undervacuum, washed with diethyl ether, dried under vacuum at 50° C. for 14hours, and analyzed by XRPD (see FIG. 4A), TGA/EGA and DSC.

Example II.4.2 Preparation of fumarate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form

30.91 mg of fumaric acid was dissolved in 2 ml methanol under stirringuntil complete dissolution. 50 mg free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate was added to the solution and themixture was stirred at room temperature until complete dissolution. Thesolvents were evaporated at room temperature for 3 days and a yellow oilwas obtained. 1 ml acetone was added and the mixture stirred at roomtemperature for 2 hours. A yellow precipitate was recovered undervacuum, washed with diethyl ether, dried under vacuum at 50° C. for 14hours, and analyzed by XRPD (see FIG. 4A), TGA/EGA and DSC.

The following are further embodiments of the invention:

Embodiment 1

A free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in solid form; or a salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in solid form, wherein said salt isthe citrate, hydrochloride, fumarate, adipate, maleate or sebacate of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate.

Embodiment 2

A free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in solid form.

Embodiment 3

The free form according to embodiment 2, wherein the free form is incrystalline form.

Embodiment 4

The free form according to embodiment 3, wherein the free form ischaracterized by an XRPD pattern substantially the same as the XRPDpattern shown in FIG. 1A.

Embodiment 5

The free form according to any one of embodiments 2 to 4, wherein thefree form is in substantially pure form.

Embodiment 6

The free form according to any one of embodiments 2 to 4, wherein thefree form has a purity greater than 90 weight %.

Embodiment 7

A salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in solid form, wherein said salt isthe citrate, hydrochloride, fumarate, adipate, maleate or sebacate of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate.

Embodiment 8

The salt according to embodiment 7, wherein the salt is the citrate of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form.

Embodiment 9

The salt according to embodiment 8, wherein the salt is characterized byan XRPD pattern substantially the same as the XRPD pattern shown in FIG.2A.

Embodiment 10

The salt according to any one of embodiments 7 to 9, wherein the salt isin substantially pure form.

Embodiment 11

The salt according to any one of embodiments 7 to 9, wherein the salthas a purity greater than 90 weight %.

Embodiment 12

A pharmaceutical composition, which comprises a free form as defined inany one of embodiments 2 to 6 as active ingredient and at least onepharmaceutically acceptable carrier.

Embodiment 13

A pharmaceutical composition, which comprises a salt as defined in anyone of claims 7 to 11 as active ingredient and at least onepharmaceutically acceptable carrier.

Embodiment 14

A method of preparing a citrate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form comprising thesteps of

(a) preparing a solution of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate and citric acid in acetone, whereinthe 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate:citric acid ratio is about 1:2;(b) adding to the solution of step (a) an ether antisolvent, e.g.diethyl ether, until an acetone:ether antisolvent volume ratio from 1:1to 1:5 is reached; and(e) isolate the solids by filtration to obtain the citrate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form.

Embodiment 15

A method of preparing a hydrochloride salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form comprising thesteps of

(a) preparing a solution of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in acetone;(b) adding to the solution of step (a) hydrochloric acid until a1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate:hydrochloric acid ratio of about1:1 is reached; and(e) isolate the solids by filtration to obtain the hydrochloride salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate in crystalline form.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows the XRPD pattern for Form A of the free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate. The x-axis represents the angle ofrefraction 2-theta, wherein a scale mark corresponds to 2.5 2-theta andwherein the first scale mark is 5.0 2-theta. The y-axis representsIntensity (counts), wherein a scale mark corresponds to 2500 counts andwherein the first scale mark is 2500 counts.

FIG. 1B shows the XRPD pattern for Form B of the free form of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate. The x-axis represents the angle ofrefraction 2-theta, wherein a scale mark corresponds to 2.5 2-theta andwherein the first scale mark is 5.0 2-theta. The y-axis representsIntensity (counts), wherein a scale mark corresponds to 1000 counts andwherein the first scale mark is 1000 counts.

FIG. 2A shows the XRPD pattern for Form A of the citrate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate. The x-axis represents the angle ofrefraction 2-theta, wherein a scale mark corresponds to 1.0 2-theta andwherein the first scale mark is 3.0 2-theta. The y-axis represents Lin(Counts), wherein a scale mark corresponds to 1 count and wherein thefirst scale mark is 1 count.

FIG. 2B shows the proton-NMR spectrum for Form A of the citrate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate The x-axis represents the ChemicalShift (ppm), wherein a scale mark corresponds to 0.05 ppm and whereinthe first scale mark is 8.45 ppm. The y-axis represents NormalizedIntensity, wherein a scale mark corresponds to 0.005 and wherein thefirst scale mark is −0.02.

FIG. 2C shows the XRPD pattern for Form B of the citrate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate. The x-axis represents the angle ofrefraction 2-theta, wherein a scale mark corresponds to 2.5 2-theta andwherein the first scale mark is 5.0 2-theta. The y-axis representsIntensity (counts), wherein a scale mark corresponds to 250 counts andwherein the first scale mark is 250 counts.

FIG. 3A shows the XRPD pattern for Form A of the hydrochloride salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate. The x-axis represents the angle ofrefraction 2-theta, wherein a scale mark corresponds to 1.0 2-theta andwherein the first scale mark is 3.0 2-theta. The y-axis represents Lin(Counts), wherein a scale mark corresponds to 5 counts and wherein thefirst scale mark is 5 counts.

FIG. 3B shows the XRPD pattern for Form B of the hydrochloride salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate. The x-axis represents the angle ofrefraction 2-theta, wherein a scale mark corresponds to 2.5 2-theta andwherein the first scale mark is 5.0 2-theta. The y-axis representsIntensity (counts), wherein a scale mark corresponds to 100 counts andwherein the first scale mark is 100 counts.

FIG. 4A shows the XRPD pattern for Form A of the fumarate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate. The x-axis represents the angle ofrefraction 2-theta, wherein a scale mark corresponds to 2.5 2-theta andwherein the first scale mark is 5.0 2-theta. The y-axis representsIntensity (counts), wherein a scale mark corresponds to 1000 counts andwherein the first scale mark is 1000 counts.

FIG. 4B shows the XRPD pattern for Form B of the fumarate salt of1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl4-cyclobutylpiperazine-1-carboxylate. The x-axis represents the angle ofrefraction 2-theta, wherein a scale mark corresponds to 2.5 2-theta andwherein the first scale mark is 5.0 2-theta. The y-axis representsIntensity (counts), wherein a scale mark corresponds to 250 counts andwherein the first scale mark is 250 counts.

1. A compound of the formula I

or a salt thereof, wherein R₁ is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkinyl, C₃₋₆cycloalkyl, C₆₋₆cycloalkenyl or C₃₋₆cycloalkyl-C₁₋₄alkyl; wherein said C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkinyl or C₃₋₆cycloalkyl-C₁₋₄alkyl may be substituted once or more than once by halogen; and wherein said C₃₋₆cycloalkyl or C₅₋₆cycloalkenyl may be substituted once or more than once by halogen, C₁₋₄alkyl or C₁₋₆halogenalkyl; m is 1 or 2; n is 0, 1, 2, 3 or 4; each R₂ independently is halogen, hydroxyl, amino, cyano, nitro, C₁₋₆alkyl, C₁₋₆halogenalkyl, C₁₋₆hydroxyalkyl, C₁₋₄alkoxy-C₁₋₆alkyl, amino-C₁₋₆alkyl, C₁₋₄alkyl-amino-C₁₋₆alkyl, di(C₁₋₄alkyl)-amino-C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆halogenalkoxy, di(C₁₋₆alkyl)amino, C₂₋₆alkenyl, C₂₋₆halogenalkenyl, C₂₋₆alkinyl or C₂₋₆halogenalkinyl; or C₃₋₆cycloalkyl, wherein one carbon atom may be replaced by an oxygen atom, wherein the C₃₋₆cycloalkyl may be attached directly to the methylene or via a C₁₋₂alkylene, and wherein the C₃₋₆cycloalkyl may be substituted once or more than once by halogen; or two R₂ at the same carbon atom form together with said carbon atom a C₃₋₆cycloalkyl; X₁ is oxygen or —N(R₄)—; R₄ is hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, or C₃₋₆cycloalkyl-C₁₋₂alkyl; p is 1 and q is 1; p is 0 and q is 1; or p is 0 and q is 0; r is 0, 1, 2, 3 or 4; each R₃ independently is halogen, hydroxyl, amino, cyano, nitro, C₁₋₆alkyl, C₁₋₆halogenalkyl, C₁₋₆hydroxyalkyl, C₁₋₄alkoxy-C₁₋₆alkyl, amino-C₁₋₆alkyl, C₁₋₄alkyl-amino-C₁₋₆alkyl, di(C₁₋₄alkyl)-amino-C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆halogenalkoxy, di(C₁₋₆alkyl)amino, C₂₋₆alkenyl, C₂₋₆halogenalkenyl, C₂₋₆alkinyl or C₂₋₆halogenalkinyl; or C₃₋₆cycloalkyl, wherein one carbon atom may be replaced by an oxygen atom, wherein the C₃₋₆cycloalkyl may be attached directly to the methylene or via a C₁₋₂alkylene, and wherein the C₃₋₆cycloalkyl may be substituted once or more than once by halogen; or two R₃ at the same carbon atom form together with said carbon atom a C₃₋₆cycloalkyl; A is

wherein the bond marked with the asterisk is attached to the nitrogen atom; R₅ is hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkinyl, C₃₋₆cycloalkyl, C₅₋₆cycloalkenyl or C₃₋₆cycloalkyl-C₁₋₄alkyl; wherein said C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkinyl or C₃₋₆cycloalkyl-C₁₋₄alkyl may be substituted once or more than once by halogen, hydroxyl or C₁₋₆alkoxy; and wherein said C₃₋₆cycloalkyl or C₅₋₆cycloalkenyl may be substituted once or more than once by halogen, C₁₋₄alkyl or C₁₋₄halogenalkyl; X₂ is nitrogen or carbon; s is 0, 1, 2 or 3; each R₆ independently is halogen, hydroxyl, amino, cyano, nitro, C₁₋₆alkyl, C₁₋₆halogenalkyl, C₁₋₆hydroxyalkyl, C₁₋₄alkoxy-C₁₋₆alkyl, amino-C₁₋₆alkyl, C₁₋₄alkyl-amino-C₁₋₆alkyl, di(C₁₋₄alkyl)-amino-C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆halogenalkoxy, di(C₁₋₆alkyl)amino, C₂₋₆alkenyl, C₂₋₆halogenalkenyl, C₂₋₆alkinyl or C₂₋₆halogenalkinyl; or C₃₋₆cycloalkyl, wherein one carbon atom may be replaced by an oxygen atom, wherein the C₃₋₆cycloalkyl may be attached directly to the methylene or via a C₁₋₂alkylene, and wherein the C₃₋₆cycloalkyl may be substituted once or more than once by halogen.
 2. A compound of formula I according to claim 1, wherein X₁ is oxygen; or a salt thereof.
 3. A compound of formula I according to claim 1, wherein p is 1 and q is 1; or a salt thereof.
 4. A compound of formula I according to claim 1, wherein R₁ is isopropyl, cyclopropyl, cyclobutyl or cyclopentyl and m is 1; or a salt thereof.
 5. A compound of formula I according claim 1, wherein A is selected from A3 and A4

wherein the bond marked with the asterisk is attached to the nitrogen atom; or a salt thereof.
 6. A compound of formula I according to claim 1, wherein R₁ is isopropyl or cyclobutyl; m is 1; n is 0, 1 or 2; each R₂ independently is halogen, C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄alkoxy, C₁₋₄halogenalkoxy or C₃₋₄cycloalkyl; or two R₂ at the same carbon atom form together with said carbon atom a C₃₋₄cycloalkyl; X₁ is oxygen; p is 1 and q is 1; r is 0, 1 or 2; wherein each R₃ independently is halogen, C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄alkoxy, C₁₋₄halogenalkoxy or C₃₋₄cycloalkyl; or two R₃ at the same carbon atom form together with said carbon atom a C₃₋₄cycloalkyl; A is selected from A3 and A4

wherein the bond marked with the asterisk is attached to the nitrogen atom; R₅ is hydrogen or methyl; s is 0, 1 or 2; and each R₆ independently is halogen, C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄alkoxy, C₁₋₄halogenalkoxy or C₃₋₄cycloalkyl; or a salt thereof.
 7. A compound of formula I according to claim 1, wherein said compound is selected from the group consisting of 1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate; 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate; 1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate; 1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclopropylpiperazine-1-carboxylate; 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate; 1-(1-ethyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate; 1-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate; 1-(2-oxo-1,2-dihydropyridin-4-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate; 1-(2-oxo-1,2-dihydropyridin-4-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate; and 1-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate; or salts of these compounds.
 8. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and one or more pharmaceutically acceptable carriers.
 9. A combination comprising a therapeutically effective amount of the compound according to claim 1 and one or more therapeutically active agents.
 10. A method of treating a disorder or a disease in a subject mediated by H3 receptors, wherein the method comprises administering to the subject a therapeutically effective amount of a compound according to claim
 1. 11. A compound according to claim 1, for use as a medicament.
 12. Use of a compound according to claim 1, for the treatment of a disorder or disease in a subject mediated by H3 receptors.
 13. Use of a compound according to claim 1, for the treatment of a disorder or disease in a subject characterized by an abnormal activity of H3 receptors.
 14. A compound of formula II-1

or a salt thereof; in which p, q, r, R₃ and A are as defined under formula I; and R_(a) is a leaving group.
 15. A free form of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in solid form; or a salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in solid form, wherein said salt is the citrate, hydrochloride, fumarate, adipate, maleate or sebacate of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate.
 16. A pharmaceutical composition, which comprises a free form or a salt as defined in claim 15 as active ingredient and at least one pharmaceutically acceptable carrier.
 17. A method of preparing a citrate salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form comprising the steps of (a) preparing a solution of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate and citric acid in acetone, wherein the 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate:citric acid ratio is about 1:2; (b) adding to the solution of step (a) an ether antisolvent, e.g. diethyl ether, until an acetone:ether antisolvent volume ratio from 1:1 to 1:5 is reached; and (e) isolate the solids by filtration to obtain the citrate salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form. 